Non-metastatic castrate-resistant prostate cancer: a call for improved guidance on clinical management.

BACKGROUND Guidelines on the clinical management of non-metastatic castrate-resistant prostate cancer (nmCRPC) generally focus on the need to continue androgen deprivation therapy and enrol patients into clinical trials of investigational agents. This guidance reflects the lack of clinical trial data with established agents in the nmCRPC patient population and the need for trials of new agents. AIM To review the evidence base and consider ways of improving the management of nmCRPC. CONCLUSION Upon the development of castrate resistance, it is essential to rule out the presence of metastases or micrometastases by optimising the use of bone scans and possibly newer procedures and techniques. When nmCRPC is established, management decisions should be individualised according to risk, but risk stratification in this diverse population is poorly defined. Currently, prostate-specific antigen (PSA) levels and PSA doubling time remain the best method of assessing the risk of progression and response to treatment in nmCRPC. However, optimising imaging protocols can also help assess the changing metastatic burden in patients with CRPC. Clinical trials of novel agents in nmCRPC are limited and have problems with enrolment, and therefore, improved risk stratification and imaging may be crucial to the improved management. The statements presented in this paper, reflecting the views of the authors, provide a discussion of the most recent evidence in nmCRPC and provide some advice on how to ensure these patients receive the best management available. However, there is an urgent need for more data on the management of nmCRPC.

Small-diameter titanium grade IV and titanium-zirconium implants in edentulous mandibles: five-year results from a double-blind, randomized controlled trial.

BACKGROUND The aim of this study was to compare the 5-year survival and success rates of 3.3 mm dental implants either made from titanium-zirconium (TiZr) alloy or from Grade IV titanium (Ti Grade IV) in mandibular implant-based removable overdentures. METHODS The core study had a follow-up period of 36 months and was designed as a randomized, controlled, double-blind, split-mouth multicenter clinical trial. Patients with edentulous mandibles received two Straumann Bone Level implants (diameter 3.3 mm, SLActive®), one of TiZr (test) and one of Ti Grade IV (control), in the interforaminal region. This follow-up study recruited patients from the core study and evaluated the plaque and sulcus bleeding indices, radiographic crestal bone level, as well as implant survival and success 60 months after implant placement. RESULTS Of the 91 patients who initially received implants, 75 completed the 36 month follow-up and 49 were available for the 60 month examination. Two patients were excluded so that a total of 47 patients with an average age of 72 ± 8 years were analysed. The characteristics and 36-month performance of the present study cohort did not differ from the non-included initial participants (p > 0.05). In the period since the 36-month follow-up examination, no implant was lost. The cumulative implant survival rate was 98.9 % for the TiZr group and 97.8 % for the Ti Grade IV group. Crestal bone level changes at 60 months were not different in the test and control group (TiZr -0.60 ± 0.69 mm and Ti Grade IV -0.61 ± 0.83 mm; p = 0.96). The cumulative implant success rate after 60 months was 95.8 and 92.6 % for TiZr and Ti Grade IV, respectively. CONCLUSIONS After 60 months, the positive outcomes of the 36 month results for TiZr and Ti Grade IV implants were confirmed, with no significant differences with regard to crestal bone level change, clinical parameters and survival or success rates. TiZr implants performed equally well compared to conventional Ti Grade IV 3.3 mm diameter-reduced implants for mandibular removable overdentures. TRIAL REGISTRATION Registered on www.clinicaltrials.gov: NCT01878331.

Small-diameter titanium Grade IV and titanium-zirconium implants in edentulous mandibles: three-year results from a double-blind, randomized controlled trial

OBJECTIVE The aim of this study was to compare crestal bone-level changes, soft tissue parameters and implant success and survival between small-diameter implants made of titanium/zirconium (TiZr) alloy or of Grade IV titanium (Ti) in edentulous mandibles restored with removable overdentures. MATERIALS AND METHODS This was a randomized, controlled, double-blind, split-mouth multicenter clinical trial. Patients with edentulous mandibles received two Straumann bone-level implants (diameter 3.3 mm), one of Ti Grade IV (control) and one of TiZr (test), in the interforaminal region. Implants were loaded after 6-8 weeks and removable Locator-retained overdentures were placed within 2 weeks of loading. Modified plaque and sulcus bleeding indices, radiographic bone level, and implant survival and success were evaluated up to 36 months. RESULTS Of 91 treated patients, 75 completed the three-year follow-up. Three implants were lost (two control and one test implant). The survival rates were 98.7% and 97.3%, and the mean marginal bone level change was -0.78 ± 0.75 and -0.60 ± 0.71 mm for TiZr and Ti Grade IV implants. Most patients had a plaque score of 0 or 1 (54% for test and 51.7% for control), and a sulcus bleeding score of 0 (46.1% for test and 44.9% for control). No significant differences were found between the two implant types for bone-level change, soft tissue parameters, survival and success. CONCLUSIONS After 36 months, similar outcomes were found between Ti Grade IV and TiZr implants. The results confirm that the results seen at 12 months continue over time.

Preprocedural High-Sensitivity Cardiac Troponin T and Clinical Outcomes in Patients With Stable Coronary Artery Disease Undergoing Elective Percutaneous Coronary Intervention.

BACKGROUND Cardiac troponin detected by new-generation, highly sensitive assays predicts clinical outcomes among patients with stable coronary artery disease (SCAD) treated medically. The prognostic value of baseline high-sensitivity cardiac troponin T (hs-cTnT) elevation in SCAD patients undergoing elective percutaneous coronary interventions is not well established. This study assessed the association of preprocedural levels of hs-cTnT with 1-year clinical outcomes among SCAD patients undergoing percutaneous coronary intervention. METHODS AND RESULTS Between 2010 and 2014, 6974 consecutive patients were prospectively enrolled in the Bern Percutaneous Coronary Interventions Registry. Among patients with SCAD (n=2029), 527 (26%) had elevated preprocedural hs-cTnT above the upper reference limit of 14 ng/L. The primary end point, mortality within 1 year, occurred in 20 patients (1.4%) with normal hs-cTnT versus 39 patients (7.7%) with elevated baseline hs-cTnT (P<0.001). Patients with elevated hs-cTnT had increased risks of all-cause (hazard ratio 5.73; 95% confidence intervals 3.34-9.83; P<0.001) and cardiac mortality (hazard ratio 4.68; 95% confidence interval 2.12-10.31; P<0.001). Preprocedural hs-TnT elevation remained an independent predictor of 1-year mortality after adjustment for relevant risk factors, including age, sex, and renal failure (adjusted hazard ratio 2.08; 95% confidence interval 1.10-3.92; P=0.024). A graded mortality risk was observed across higher tertiles of elevated preprocedural hs-cTnT, but not among patients with hs-cTnT below the upper reference limit. CONCLUSIONS Preprocedural elevation of hs-cTnT is observed in one fourth of SCAD patients undergoing elective percutaneous coronary intervention. Increased levels of preprocedural hs-cTnT are proportionally related to the risk of death and emerged as independent predictors of all-cause mortality within 1 year. CLINICAL TRIAL REGISTRATION URL: http://www.clinicaltrials.gov. Unique identifier: NCT02241291.

Bayesian doubly optimal group sequential designs for randomized clinical trials

When conducting a randomized comparative clinical trial, ethical, scientific or economic considerations often motivate the use of interim decision rules after successive groups of patients have been treated. These decisions may pertain to the comparative efficacy or safety of the treatments under study, cost considerations, the desire to accelerate the drug evaluation process, or the likelihood of therapeutic benefit for future patients. At the time of each interim decision, an important question is whether patient enrollment should continue or be terminated; either due to a high probability that one treatment is superior to the other, or a low probability that the experimental treatment will ultimately prove to be superior. The use of frequentist group sequential decision rules has become routine in the conduct of phase III clinical trials. In this dissertation, we will present a new Bayesian decision-theoretic approach to the problem of designing a randomized group sequential clinical trial, focusing on two-arm trials with time-to-failure outcomes. Forward simulation is used to obtain optimal decision boundaries for each of a set of possible models. At each interim analysis, we use Bayesian model selection to adaptively choose the model having the largest posterior probability of being correct, and we then make the interim decision based on the boundaries that are optimal under the chosen model. We provide a simulation study to compare this method, which we call Bayesian Doubly Optimal Group Sequential (BDOGS), to corresponding frequentist designs using either O'Brien-Fleming (OF) or Pocock boundaries, as obtained from EaSt 2000. Our simulation results show that, over a wide variety of different cases, BDOGS either performs at least as well as both OF and Pocock, or on average provides a much smaller trial. ^

Interim analysis of clinical trials: Simulation studies of fractional Brownian motion

Interim clinical trial monitoring procedures were motivated by ethical and economic considerations. Classical Brownian motion (Bm) techniques for statistical monitoring of clinical trials were widely used. Conditional power argument and α-spending function based boundary crossing probabilities are popular statistical hypothesis testing procedures under the assumption of Brownian motion. However, it is not rare that the assumptions of Brownian motion are only partially met for trial data. Therefore, I used a more generalized form of stochastic process, called fractional Brownian motion (fBm), to model the test statistics. Fractional Brownian motion does not hold Markov property and future observations depend not only on the present observations but also on the past ones. In this dissertation, we simulated a wide range of fBm data, e.g., H = 0.5 (that is, classical Bm) vs. 0.5< H <1, with treatment effects vs. without treatment effects. Then the performance of conditional power and boundary-crossing based interim analyses were compared by assuming that the data follow Bm or fBm. Our simulation study suggested that the conditional power or boundaries under fBm assumptions are generally higher than those under Bm assumptions when H > 0.5 and also matches better with the empirical results. ^

Hypotensive resuscitation versus standard fluid resuscitation for the management of trauma patients in hemorrhagic shock: The safety phase of a randomized controlled trial

Trauma is a leading cause of death worldwide, and is thus a major public health concern. Improving current resuscitation strategies may help to reduce morbidity and mortality from trauma, and clinical research plays an important role in addressing these issues. This thesis is a secondary analysis of data that was collected for a randomized clinical trial being conducted at Ben Taub General Hospital. The trial is designed to compare a hypotensive resuscitation strategy to standard fluid resuscitation for the early treatment of trauma patients in hemorrhagic shock. This thesis examines the clinical outcomes from the first 90 subjects enrolled in the study, with the primary aim of assessing the safety of hypotensive resuscitation within the trauma population. ^ Patients in hemorrhagic shock who required emergent surgery were randomized to one of two arms of the study. Those in the experimental (LMAP) arm were managed with a hypotensive resuscitation strategy in which the target mean arterial pressure was 50mmHg. Those in the control (HMAP) arm were managed with standard fluid resuscitation to a target mean arterial pressure of 65mmHg. Patients were followed for 30 days. Mortality, post-operative complications, and other clinical data were prospectively gathered by the Ben Taub surgical staff and then secondarily analyzed for the purpose of this thesis.^ Subjects in the LMAP group had significantly lower early post-operative mortality compared to those in the HMAP group. 30-day mortality was also lower in the LMAP group, although this did not reach statistical significance. There were no statistically significant differences between the two groups with regards to development of ischemic, hematologic or infectious complications, length of hospitalization, length of ICU stay or duration of mechanical ventilation. ^ Based upon the data presented in this thesis, it appears that hypotensive resuscitation is a safe strategy for use in the trauma population. Specifically, hypotensive resuscitation reduced the risk of early post-operative death from coagulopathic bleeding and did not result in an increased risk of ischemic or other post-operative complications. The preliminary results described in this thesis provide convincing evidence support the continued investigation and use of hypotensive resuscitation in a trauma setting.^

Factors contributing to the attrition of women in the African-American Nutrition for Life study

Background. There is currently a push to increase the number of minorities in cancer clinical trials in an effort to reduce cancer health disparities. Overcoming barriers to clinical trial research for minorities is necessary if we are to achieve the goals of Healthy People 2010. To understand the unexpectedly high rate of attrition in the A NULIFE study, the research team examined the perceived barriers to participation among minority women. The purpose of this study was to determine if either personal or study-related factors influenced healthy pre-menopausal women aged 25-45 years to terminate their participation in the A NULIFE Study. We hypothesized that personal factors were the driving forces for attrition rates in the prevention trial.^ Methods. The target population consisted of eligible women who consented to the A NULIFE study but withdrew prior to being randomized (N= 46), as well as eligible women who completed the informed consent process for the A NULIFE study and withdrew after randomization (N= 42). Examination of attrition rates in this study occurred at a time point when 10 out of 12 participant groups had completed the A NULIFE study. Data involving the 2 groups that were actively engaged in study activities were not used in this analysis. A survey instrument was designed to query the personal and study-related factors that were believed to have contributed to the decision to terminate participation in the A NULIFE study.^ Results. Overall, the highest ranked personal reason that influenced withdrawal from the study was being “too busy” with other obligations. The second highest ranked factor for withdrawal was work obligations. Whereas, more than half of all participants agreed that they were well-informed about the study and considered the study personnel to be approachable, 54% of participants would have been inclined to remain in the study if it were located at a local community center.^ Conclusions. Time commitment was likely a major factor for withdrawal from the A NULIFE study. Future investigators should implement trials within participant communities where possible. Also, focus group settings may provide detailed insight into factors that contribute to the attrition of minorities in cancer clinical trials.^

Physical activity among breast and prostate cancer survivors: Barriers, facilitators and maintenance following the FRESH START trial

Research provides evidence of the positive health effects associated with regular physical activity participation in all populations. Activity may prove to be especially beneficial in those with chronic conditions such as cancer. However, the majority of cancer patients and survivors do not participate in the recommended amount of physical activity. The purpose of this dissertation was to identify factors associated with physical activity participation, describe how these factors change as result of a diet and exercise intervention, and to evaluate correlates of long term physical activity maintenance. ^ For this dissertation, I analyzed data from the FRESH START trial, a randomized, single-blind, phase II clinical trial focused on improving diet and physical activity among recently diagnosed breast and prostate cancer survivors. Analyses included both parametric and non-parametric statistical tests. Three separate studies were conducted, with sample sizes ranging from 400 to 486. ^ Common barriers to exercise, such as “no willpower,” “too busy,” and “I have pain,” were reported among breast and prostate cancer survivors; however, these barriers were not significantly associated with minutes of physical activity. Breast cancer survivors reported a greater number of total barriers to exercise as well as higher proportions reporting individual barriers, compared to prostate cancer survivors. Just less than half of participants reduced their total number of barriers to exercise from baseline to 1-year follow-up, and those who did reduce barriers reported greater increases in minutes of physical activity compared to those who reported no change in barriers to exercise. Participants in both the tailored and standardized intervention groups reported greater minutes of physical activity at 2-year follow-up compared to baseline. Overall, twelve percent of participants reached recommended levels of physical activity at both 1- and 2-year follow-up. Self-efficacy was positively associated with physical activity maintenance, and the number of total barriers to exercise was inversely associated with physical activity maintenance. ^ Results from this dissertation are novel and informative, and will help to guide future physical activity interventions among cancer survivors. Thoughtfully designed interventions may encourage greater participation in physical activity and ultimately improve overall quality of life in this population. ^

Effect of patient accrual patterns on power and size of log-rank test for time-to-event outcome in clinical trials

The determination of size as well as power of a test is a vital part of a Clinical Trial Design. This research focuses on the simulation of clinical trial data with time-to-event as the primary outcome. It investigates the impact of different recruitment patterns, and time dependent hazard structures on size and power of the log-rank test. A non-homogeneous Poisson process is used to simulate entry times according to the different accrual patterns. A Weibull distribution is employed to simulate survival times according to the different hazard structures. The current study utilizes simulation methods to evaluate the effect of different recruitment patterns on size and power estimates of the log-rank test. The size of the log-rank test is estimated by simulating survival times with identical hazard rates between the treatment and the control arm of the study resulting in a hazard ratio of one. Powers of the log-rank test at specific values of hazard ratio (≠1) are estimated by simulating survival times with different, but proportional hazard rates for the two arms of the study. Different shapes (constant, decreasing, or increasing) of the hazard function of the Weibull distribution are also considered to assess the effect of hazard structure on the size and power of the log-rank test. ^

Bayesian adaptive designs in early phase clinical trials

There are two practical challenges in the phase I clinical trial conduct: lack of transparency to physicians, and the late onset toxicity. In my dissertation, Bayesian approaches are used to address these two problems in clinical trial designs. The proposed simple optimal designs cast the dose finding problem as a decision making process for dose escalation and deescalation. The proposed designs minimize the incorrect decision error rate to find the maximum tolerated dose (MTD). For the late onset toxicity problem, a Bayesian adaptive dose-finding design for drug combination is proposed. The dose-toxicity relationship is modeled using the Finney model. The unobserved delayed toxicity outcomes are treated as missing data and Bayesian data augment is employed to handle the resulting missing data. Extensive simulation studies have been conducted to examine the operating characteristics of the proposed designs and demonstrated the designs' good performances in various practical scenarios.^

A simulation study of the standard design, the rolling six design, the CRM, and the modified CRM in Phase I clinical trials

The Phase I clinical trial is considered the "first in human" study in medical research to examine the toxicity of a new agent. It determines the maximum tolerable dose (MTD) of a new agent, i.e., the highest dose in which toxicity is still acceptable. Several phase I clinical trial designs have been proposed in the past 30 years. The well known standard method, so called the 3+3 design, is widely accepted by clinicians since it is the easiest to implement and it does not need a statistical calculation. Continual reassessment method (CRM), a design uses Bayesian method, has been rising in popularity in the last two decades. Several variants of the CRM design have also been suggested in numerous statistical literatures. Rolling six is a new method introduced in pediatric oncology in 2008, which claims to shorten the trial duration as compared to the 3+3 design. The goal of the present research was to simulate clinical trials and compare these phase I clinical trial designs. Patient population was created by discrete event simulation (DES) method. The characteristics of the patients were generated by several distributions with the parameters derived from a historical phase I clinical trial data review. Patients were then selected and enrolled in clinical trials, each of which uses the 3+3 design, the rolling six, or the CRM design. Five scenarios of dose-toxicity relationship were used to compare the performance of the phase I clinical trial designs. One thousand trials were simulated per phase I clinical trial design per dose-toxicity scenario. The results showed the rolling six design was not superior to the 3+3 design in terms of trial duration. The time to trial completion was comparable between the rolling six and the 3+3 design. However, they both shorten the duration as compared to the two CRM designs. Both CRMs were superior to the 3+3 design and the rolling six in accuracy of MTD estimation. The 3+3 design and rolling six tended to assign more patients to undesired lower dose levels. The toxicities were slightly greater in the CRMs.^

Modified 3+3 design for phase I clinical trials

Phase I clinical trial is mainly designed to determine the maximum tolerated dose (MTD) of a new drug. Optimization of phase I trial design is crucial to minimize the number of enrolled patients exposed to unsafe dose levels and to provide reliable information to the later phases of clinical trials. Although it has been criticized about its inefficient MTD estimation, nowadays the traditional 3+3 method remains dominant in practice due to its simplicity and conservative estimation. There are many new designs that have been proven to generate more credible MTD estimation, such as the Continual Reassessment Method (CRM). Despite its accepted better performance, the CRM design is still not widely used in real trials. There are several factors that contribute to the difficulties of CRM adaption in practice. First, CRM is not widely accepted by the regulatory agencies such as FDA in terms of safety. It is considered to be less conservative and tend to expose more patients above the MTD level than the traditional design. Second, CRM is relatively complex and not intuitive for the clinicians to fully understand. Third, the CRM method take much more time and need statistical experts and computer programs throughout the trial. The current situation is that the clinicians still tend to follow the trial process that they are comfortable with. This situation is not likely to change in the near future. Based on this situation, we have the motivation to improve the accuracy of MTD selection while follow the procedure of the traditional design to maintain simplicity. We found that in 3+3 method, the dose transition and the MTD determination are relatively independent. Thus we proposed to separate the two stages. The dose transition rule remained the same as 3+3 method. After getting the toxicity information from the dose transition stage, we combined the isotonic transformation to ensure the monotonic increasing order before selecting the optimal MTD. To compare the operating characteristics of the proposed isotonic method and the other designs, we carried out 10,000 simulation trials under different dose setting scenarios to compare the design characteristics of the isotonic modified method with standard 3+3 method, CRM, biased coin design (BC) and k-in-a-row design (KIAW). The isotonic modified method improved MTD estimation of the standard 3+3 in 39 out of 40 scenarios. The improvement is much greater when the target is 0.3 other than 0.25. The modified design is also competitive when comparing with other selected methods. A CRM method performed better in general but was not as stable as the isotonic method throughout the different dose settings. The results demonstrated that our proposed isotonic modified method is not only easily conducted using the same procedure as 3+3 but also outperforms the conventional 3+3 design. It can also be applied to determine MTD for any given TTL. These features make the isotonic modified method of practical value in phase I clinical trials.^

A simulation study of the effects of small center enrollment in multi -center clinical trials

Multi-center clinical trials are very common in the development of new drugs and devices. One concern in such trials, is the effect of individual investigational sites enrolling small numbers of patients on the overall result. Can the presence of small centers cause an ineffective treatment to appear effective when treatment-by-center interaction is not statistically significant?^ In this research, simulations are used to study the effect that centers enrolling few patients may have on the analysis of clinical trial data. A multi-center clinical trial with 20 sites is simulated to investigate the effect of a new treatment in comparison to a placebo treatment. Twelve of these 20 investigational sites are considered small, each enrolling less than four patients per treatment group. Three clinical trials are simulated with sample sizes of 100, 170 and 300. The simulated data is generated with various characteristics, one in which treatment should be considered effective and another where treatment is not effective. Qualitative interactions are also produced within the small sites to further investigate the effect of small centers under various conditions.^ Standard analysis of variance methods and the "sometimes-pool" testing procedure are applied to the simulated data. One model investigates treatment and center effect and treatment-by-center interaction. Another model investigates treatment effect alone. These analyses are used to determine the power to detect treatment-by-center interactions, and the probability of type I error.^ We find it is difficult to detect treatment-by-center interactions when only a few investigational sites enrolling a limited number of patients participate in the interaction. However, we find no increased risk of type I error in these situations. In a pooled analysis, when the treatment is not effective, the probability of finding a significant treatment effect in the absence of significant treatment-by-center interaction is well within standard limits of type I error. ^

Identifying the semantics of eligibility criteria of clinical trials based on relevant medical ontologies

An important objective of the INTEGRATE project1 is to build tools that support the efficient execution of post-genomic multi-centric clinical trials in breast cancer, which includes the automatic assessment of the eligibility of patients for available trials. The population suited to be enrolled in a trial is described by a set of free-text eligibility criteria that are both syntactically and semantically complex. At the same time, the assessment of the eligibility of a patient for a trial requires the (machineprocessable) understanding of the semantics of the eligibility criteria in order to further evaluate if the patient data available for example in the hospital EHR satisfies these criteria. This paper presents an analysis of the semantics of the clinical trial eligibility criteria based on relevant medical ontologies in the clinical research domain: SNOMED-CT, LOINC, MedDRA. We detect subsets of these widely-adopted ontologies that characterize the semantics of the eligibility criteria of trials in various clinical domains and compare these sets. Next, we evaluate the occurrence frequency of the concepts in the concrete case of breast cancer (which is our first application domain) in order to provide meaningful priorities for the task of binding/mapping these ontology concepts to the actual patient data. We further assess the effort required to extend our approach to new domains in terms of additional semantic mappings that need to be developed.