Submitted in partial fulfilment of the requirements for the degree of Master of Public Health, in the field of Social and Behaviour Change Communications, in the University of the Witwatersrand, Johannesburg, 2012 / The Good Participatory Practice Guidelines recommend that research results are made available to a broad range of stakeholders, including policy makers and trial participants, yet there is little guidance on how this may be achieved. The Microbicides Development Programme (MDP301 trial) was a large scale clinical trial that took place at thirteen clinics in South Africa, Tanzania, Uganda and Zambia between 2004 and 2009. The results of this trial were released in late 2009 and a comprehensive, multi-method results dissemination plan was implemented to communicate the research findings to policy makers, key stakeholders, research staff, Community Advisory Boards and trial participants between December 2009 and November 2010. This study was a retrospective analysis which included a process evaluation (and costing) of the implementation of the results dissemination plan for the MDP301 trial and an analysis of how the incorporation of telephonic unblinding potentially benefited the research community.

Symptoms in patients receiving dialysis are common and associated with impaired quality of life. Symptoms are a top research priority because effective therapies are lacking and even with appropriate diagnosis and treatment, residual symptoms often persist. Clinical trials in the setting of kidney disease are challenging to conduct and as a result, nephrology lags behind other specialties regarding the degree to which clinical trials inform the care of patients with kidney disease, including those receiving dialysis. The studies in this thesis inform the design of randomized controlled trials with regards to run-in periods and the treatment of symptoms in patients with kidney disease. Chapter 2 describes a meta-epidemiologic study of the frequency, setting and purposes of run-in periods in parallel randomized controlled trials of self-administered medications for chronic diseases in adults. Chapter 3 is a study within a trial of an international randomized controlled trial that compares spironolactone to placebo for the prevention of cardiovascular morbidity and mortality in dialysis. It compares the ability of a 3-week study visit in addition to a 7-week study visit during an active-run-in period to identify and exclude participants with non-adherence. Chapter 4 is a protocol for a randomized placebo controlled crossover trial of low fixed dose pharmacologic therapy for restless legs syndrome in hemodialysis that includes a placebo run-in period for adherence and tolerability. Chapter 5 is a survey of Canadian nephrologists regarding the use of cannabinoids for symptom management in patients with kidney disease and support for their use in clinical trials. / Thesis / Doctor of Philosophy (PhD)

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Due to the rapidly development in biomedical industry and the progressive needs in clinical trial, the clinical trial has remarkably increased during the past years. The composition of volunteers is not only included patients but also healthy subjects, which catered for the differences of research design of the trial. Thus, many ethical issues related to clinical trials have gained attention, particularly, the motivations of participating in clinical trials from healthy volunteers are crucial issue. The intention of the study is not only to understand the mainly motivation, perception and personality trait of healthy volunteers, but also to discuss the influence of demographic variables and personality trait on the motivation of volunteers participating clinical trials in Taiwan. This study was a cross-sectional survey research. The study sample included 196 healthy volunteers from three different biomedical clinical trial companies. The self-administered questionnaire contained 15 questions. The internal consistency reliability (£\) for the BFI scale was .789. One-way ANOVA and post-hoc analysis were used to examine the differences of the motivation in different demographic variables. In addition, hierarchical regression analysis was employed to investigate the determinants of different motivation. The results of the study showed most of the healthy volunteers were single male undergraduate students with age 20-24. The types of personality, openness¡Bextraversion and agreeableness, tended to be high tendentiousness. On the other hands, the subjects in neuroticism personality tended to be low tendentiousness. Moreover, the results showed the main motivation of the healthy volunteers is financial rewards, followed by free physical examination and the last is invitation by friends, respectively. According to the results of the study, the relatedness between the motivation of participating clinical trials and different variables showed that the elder subjects considered the free physical examination and promoting scientific and medical development as the mainly motivation, and showed less concern of companion invitation. Also, the subjects with higher education concerned the invitation by companion as less priority. Comparing with students, the waged volunteers showed less consideration of promoting scientific and medical development as motivation. Moreover, the healthy volunteer with average income between 10,000 to 19,999 NT considered mostly free physical examination, promotion of scientific and medical development and curiosity as the main motivation for the trial. The more involved in clinical trial the more consideration of other motivation and less concern of the invitation by companion. Furthermore, the subjects with more agreeableness personality trait tend to be more consideration of promoting scientific and medical development as their mainly motivation. In conclusion, the financial rewards is the priority consideration and shows remarkable influence to the motivation for the healthy volunteers, compared with the risk assessment and the consideration of personal health conditions. Thus, the clinical trials companies should balance between the rewards and health conditions. Particularly, the understandable and fully explanation as well informed consent before any trial implementation are necessary. Moreover, the researcher should be carefully concern about the health condition enrolling volunteers, in order to prevent the volunteer form harm.

Thesis (M.Tech.: Chiropractic)--Durban University of Technology, 2009 / Objective: The efficacy of manipulation as compared to placebo in the treatment of two groups of weight trainers with Acromioclavicular (AC) Joint Dysfunction. Methods: Twenty patients (n=20), using randomised sampling were allocated to two intervention groups. Patients in each group received four treatments each over a two-week period and assessed at initial, one week, two weeks and one month follow ups. Objective measures included Algometer and Inclinometer readings. Numerical Pain Rating Scales (NRS), Shoulder Rating Questionnaire (SRQ) and the Shoulder Pain and Disability Index (SPADI) measured subjective outcomes. Results: Manipulation demonstrated significant improvement in objective findings. Subjective outcomes did not show significant difference between the manipulation and placebo groups. Conclusion: Manipulation, when compared to placebo, can be considered as an effective treatment intervention for the treatment of AC joint dysfunction with particular reference to objective outcomes. Although, caution needs to be utilised in accepting this outcome due to limitations in sample size, subjective measure sensitivity and specificity as well as the stringency of the inclusion and exclusion criteria.

Background: Clinical trials represent a significant percentage of the time and cost to bring a drug through the development process and to Food and Drug Administration approval. Despite how critical these trials are to the drug development process, many studies are underpowered due to low accrual. This translates to valuable questions regarding the safety and effectiveness of new agents being left unanswered, requiring additional time and studies. A call for reform of the industry has been made by stakeholders in the clinical research enterprise; however, national change is slow. Thus sites that conduct clinical research must find methods to increase efficiency within the burdensome system currently in place. Throughout cancer centers adhering to the National Cancer Institute (NCI) Cancer Center Support Grant guidelines, efficiencies have been explored individually; however, there is a gap in knowledge on what factors affect sites system-wide. This dissertation seeks to examine factors that affect clinical trial efficiency in the areas of study activation looking at the outcome of local clinical trial accrual. Methods: Protocol and site-specific clinical trial administration data was collected regarding closed, interventional treatment and supportive care clinical trials from cancer centers adhering to NCI Cancer Center Support Grant guidelines during a five-year time period (2009-2014). Study characteristic analyses and hierarchical regression modeling was used to explore the effect of feasibility committee use and protocol workload on the outcomes of clinical trial accrual and time to activate a clinical trial. Sensitivity analyses were utilized when considering protocol workload to account for studies that had not yet closed to accrual, and thus were not included in this dataset. In addition, protocol- and site-specific variables were used to build regression models used to predict clinical trial accrual. Sensitivity, specificity, and accuracy were compared to the current standard, the institutional disease team. Results: Sixteen centers contributed a total of 5,787 protocols (range 93-697 studies). These studies accrued 49,319 subjects. Of all studies, 1,053 (18%) accrued zero subjects. Disease teams predicted 221% of actual accrual. Seven institutions submitted protocol workload information for 2,133 studies (36.9%) and 14,229 accruals (28.9%). Controlling for effect modifiers and interactions, and adjusting for institution, a statistically significant increase in clinical trial accrual and decrease in activation time was seen with the use of a feasibility committee. Regulatory protocol workload was significantly associated with clinical trial accrual and activation time; however, a single, definitive protocol workload was not identified that both minimized activation time and maximized clinical trial accrual. Protocol workload most often maximized accrual at workloads of between 3.5 and 5.0 protocols per staff member/FTE and minimized activation time at workloads between 1.0 and 1.9 protocols per staff member/FTE. Regression models predicted accrual more accurately than disease teams at all 16 centers, with site-specific models consistently having the best performance (versus an adjusted, hierarchical model). Conclusion: Despite institutional differences in variable association with accrual and activation times, the utilization of a feasibility committee was shown to improve clinical trial accrual as well as decrease activation time. Using systematic methods for examining study activation and accrual efficiencies resulted in the development of models that predicted clinical trial accrual better than the current standard (disease team prediction) at all participating centers. Further research is needed to better define and determine optimal workload. This information and these models may better inform study planning and resource allocation decisions by local stakeholders (administrators and investigators) in the clinical research enterprise.

This thesis describes the development of separate assays to measure coenzyme Q₁₀ (CoQ₁₀) and vitamin K. Coenzyme Q is essential for the mitochondrial electron transport chain, and vitamin K for the blood coagulation cascade. Vitamin K deficiency is associated with haemorrhagic disease of the new-born, and CoQ₁₀ deficiency with HMG-CoA-reductase inhibitor (statin) therapy and heart failure. Coenzyme Q and vitamin K are usually measured by HPLC, using electrochemical and ultraviolet, and electrochemical and fluorescence detection, respectively. For vitamin K1, the limit of detection achieved using fluorescence and electrochemical detection was 0.28 and 0.12 nmol/L, respectively. Sensitivity of fluorescence detection is improved by using protic solvents in the mobile phase, and platinum-black catalysed alcohol reduction. The lipophilicity and low endogenous concentrations of vitamin K1 hinder its measurement, and further work is required to produce a rapid, reliable and robust assay for its measurement in human plasma. The limits of detection achieved using fluorescence, ultraviolet and electrochemical detection to measure CoQ₁₀ were 29, 4.8, and 0.34 nmol/L, respectively. Plasma CoQ₁₀ is not stable during long term storage at -13 ℃, but at -80 ℃ it is stable for at least 18 months. The reference interval for plasma total CoQ₁₀ in the New Zealand population is 0.47 - 1.80 µmol/L. There is no clinical requirement for stratification of the reference interval according to gender. Coenzyme Q₁₀ in human plasma is homeostatically controlled, varying little over a two month interval in healthy young males. Coenzyme Q₁₀ supplements have significantly different bioavailability, with the median increase in plasma CoQ₁₀ ranging from 0.14 to 0.59 µmol/L for seven different supplement brands. There is a large inter-individual variation in CoQ₁₀ absorption, and hence plasma concentrations should be monitored during supplementation. A plateau in CoQ₁₀ absorption, from a single dose, at approximately 200 mg suggests that the maximum dose ingested at one time should be 200 mg or less. Q-Gel capsules containing 30 mg of CoQ₁₀ are twice as effective at raising blood CoQ₁₀ as 100 mg capsules. Plasma CoQ₁₀ in patients with chronic heart failure are significantly lowered by approximately 33% when these patients receive Atorvastatin for six weeks. The absolute decrease in CoQ₁₀ showed a significant correlation with worsening endothelial function (r = + 0.548, p = 0.011). Coenzyme Q₉ was shown to be present in human plasma with a reference interval of 8.8 - 47.0 nmol/L.

Background: There are a plethora of potential statistical designs which can be used to evaluate efficacy of a novel cancer treatment in the phase II clinical trial setting. Unfortunately, there is no consensus as to which design one should prefer, nor even which definition of efficacy should be used and the primary endpoint conclusion can vary depending on which design is chosen. It would be useful if an all-encompassing methodology was possible which could evaluate all the different designs simultaneously and allow investigators an understanding of the trial results under the varying scenarios. Methods: Finite Markov chain imbedding is a method which can be used in the setting of phase II oncology clinical trials but never previously evaluated in this scenario. Simple variations to the transition matrix or end-state probability definitions can be performed which allow for evaluation of multiple designs and endpoints for a single trial. A computer program is written in R which allows for computation of p-values and conditional power, two common statistical measures used for evaluation of trial results. A simulation study is performed on data arising from an actual phase II clinical trial performed recently in which the study conclusion regarding the efficacy of the potential treatment was debatable. Results: Finite Markov chain imbedding is shown to be useful for evaluating phase II oncology clinical trial results. The R code written for evaluating the simulation study is demonstrated to be fast and useful for investigating different trial designs. Further detail regarding the clinical trial results are presented, including the potential prolongation of stable disease of the treatment, which is a potentially useful marker of efficacy for this cytostatic agent. Conclusions: This novel methodology may prove to be an useful investigative technique for the evaluation of phase II oncology clinical trial data. Future studies which have disputable conclusions might become less controversial with the aid of finite Markov chain imbedding and the possible multiple evaluations which is now viable. Better understanding of activity for a given treatment might expedite the drug development process or help distinguish active from inactive treatments

The goal of this study was to determine safety, tolerability and pharmacokinetics of 2ME2 in patients with solid tumors and determine maximum tolerated dose (MTD). The following hypotheses were tested: 1) 2ME2 will be well tolerated in clinic when given orally and will have quantifiable effects on the ex vivo markers of angiogenesis and apoptosis; 2) 2ME2 will exhibit linear pharmacokinetics; 3) Plasma protein binding will be extensive and linear; 4) Sulfation will be the major metabolic pathway for 2ME2.This was a phase I dose escalation study. Twenty patients with refractory solid tumors were enrolled. 2ME2 was administered orally starting at 400 mg bid with dose escalation upto 3000 mg bid. Pharmacokinetic sampling was done up to 50 hours after single oral dose for characterization of pharmacokinetics and plasma drug concentrations which were determined by liquid chromatography tandem mass-spectrometry [LC/MS/MS, LOQ: 1ng/mL]. Circulating plasma concentrations were very low at all dose levels with high interindividual pharmacokinetic variability. Median plasma half-life was about 1-2 days. The unphysiologically high oral CL/F and Vd/F reflect low oral bioavailability of 2ME2. There was no dose proportional increase in Cmax or AUClast. There were no dose limiting toxicities at highest dose level, therefore MTD was not defined. The trial was closed due to extremely low plasma concentrations of 2ME2 achieved. Hepatic in vitro metabolism studies showed that 2ME2 was metabolized by CYP 450 enzymes (CYP 1A1, 1A2, 3A4, 3A5 and 2E1) to four major metabolites. Hepatic phase II metabolism studies revealed two major glucuronide metabolites of 2ME2. Sulfation did not play a major role in metabolism of 2ME2. Total in-vivo hepatic clearance was estimated as 862 mL/min, primarily due to glucuronidation. Less than 0.01 % of total administered dose of 2ME2 was excreted unchanged in urine, and about 1% was excreted as glucuronides. Plasma protein binding of 2ME2 was studied using equilibrium dialysis. Mean unbound fraction of 2ME2 (fu) in plasma of patients and healthy human volunteers was 0.019 ± 0.0043 and 0.027 ± 0.0019 respectively. Binding was concentration-independent and unaffected by presence of 2-methoxyestrone. 2ME2 binds to albumin, a1-acid glycoprotein (AAG) and sex-hormone binding globulin (SHBG).

In recent years, adaptive designs in clinical trials have been attractive due to their efficiency and flexibility. Response adaptive randomization procedures in phase II or III clinical trials are proposed to appeal ethical concerns by skewing the probability of patient assignments based on the responses obtained thus far, so that more patients will be assigned to a superior treatment group. General response-adaptive randomizations usually assume that the primary endpoint can be obtained quickly after the treatment. However, in real clinical trials, the primary outcome is delayed, making it unusable for adaptation. Therefore, we utilize surrogate and primary endpoints simultaneously to adaptively assign subjects between treatment groups for clinical trials with continuous responses. We explore two types of primary endpoints commonly used in clinical tirials: normally distributed outcome and time-to-event outcome. We establish a connection between the surrogate and primary endpoints through a Bayesian model, and then update the allocation ratio based on the accumulated data. Through simulation studies, we find that our proposed response adaptive randomization is more effective in assigning patients to better treatments as compared with equal allocation randomization and standard response adaptive randomization which is solely based on the primary endpoint.