Topics in clinical trial management

The aim of this thesis is to show how clinical trial conduct can be managed while respecting the underlying scientific principles. Chapter 2 describes the main results of PICO (PImobendan in COngestive heart failure), a trial which investigated a positive inotropic agent in patients with heart failure using exercise tolerance as primary outcome. The results of this trial framed our thinking about how to analyse the balance between positive and untoward effects of treatment, thinking that is further elaborated in Chapter 3. This chapter also covers issues that relate to the use of so-called combined endpoints, a feature of many recent large trials focusing on clinical outcome. Several of the lessons learnt as described in Chapter 3 were implemented while designing the ACTION (A Coronary disease Trial Investigating Outcome with Nifedipine) trial as described in Chapter 4. In Chapter 5 baseline data from the same trial are presented. At the time of writing, ACTION was still ongoing; results will be available in September 2004. In Chapter 6 we describe the database management system which was implemented to manage the ACTION study. In Chapter 7, the statistical analysis plan for this trial is reproduced. Finally, in a general discussion (Chapter 8) we focus on the trial management issues that arose during the conduct of the PICO and ACTION trials respectively. Major medical journals will publish trial results only when the “data have been gathered and are presented in an objective and dispassionate manner”.8 It follows that scientific integrity cannot be an afterthought when the trial is finished. Scientific integrity must be ensured by appropriate trial conduct from the beginning. Otherwise, the results may never see the light of day

Subconjunctival Injection of XG-102, a JNK Inhibitor Peptide, in Patients with Intraocular Inflammation: A Safety and Tolerability Study.

Abstract Purpose: We aimed to investigate the safety, tolerability, and systemic diffusion of a single escalating dose of XG-102 (a 31-D-amino-acid peptide inhibiting JNK pathway activation), administered subconjunctivally in the treatment of post-surgery or post-trauma intraocular inflammation. Methods: This is a dose-escalating, tolerance Phase Ib study. Twenty patients with post-surgery or post-traumatic intraocular inflammation were assigned to 1 of the 4 dose escalating (45, 90, 450, or 900 μg XG-102) groups of 5 patients each. Patients were evaluated at 24, 48 h, 8, and 28 days following the administration of XG-102, including laboratory tests, standard eye examinations, vital signs, and occurrence of adverse events. A single plasma quantification of XG-102 was performed 30 min after administration, according to previous pharmacokinetics studies performed on volunteers. Results: A total of 17 non-serious adverse events, considered unrelated to the study treatment, were reported for 10 patients. The adverse event incidence was not related to the drug dose. All patients experienced a decrease in intraocular inflammation as of 24 h post-administration and this decrease was sustained up to 28 days thereafter. No patient required local injection or systemic administration of corticoids following the administration of XG-102. XG-102 was undetectable in the first 3 dose groups. In the fourth-dose group (900 μg) the XG-102 plasma levels were above the limit of detection for 3 patients and above the limit of quantification for 1 patient. Conclusions: In this first clinical trial using XG-102, administered as a single subconjunctival injection as adjunct therapy, in patients with recent post-surgery or post-trauma intraocular inflammation is safe and well tolerated. Further studies are required to evaluate its efficacy

Safety of nifedipine GITS in stable angina: The ACTION trial

Aim: We describe the safety profile of nifedipine GITS as assessed from adverse events reported in the ACTION trial in which 7,665 patients with stable, symptomatic coronary artery disease were randomly assigned nifedipine GITS or placebo and followed for a mean of 4.9 years. Methods: All adverse events were coded using the COSTART coding dictionary. The incidence rate for each event was calculated as the number of patients with the event concerned divided by the total time 'at risk'. Hazard ratios comparing nifedipine with placebo and their 95% confidence intervals were obtained by Cox proportional-hazards analysis. Results: As reported previously, nifedipine significantly reduced the incidence of cardiovascular events and procedures [hazard ratio (HR) 0.89, 95% confidence interval (CI) 0.83-0.95]. Apart from the known side effects of nifedipine, which include peripheral oedema, vasodilatation, hypotension, asthenia, constipation, leg cramps, non-specific respiratory complaints, impotence and polyuria, and which were reported more frequently in patients assigned nifedipine, the incidence rates of most other adverse events were similar. There were no differences in the occurrence of gastrointestinal haemorrhage, myocardial infarction and suicide. The rate of occurrence of death or new cancer excluding non-melanoma skin cancer for patients with no history of cancer at baseline was 2.53/100 patient years for patients assigned nifedipine and 2.37/100 patient years for patients assigned placebo (HR 1.06, 95% CI 0.93-1.22). Conclusion: Overall nifedipine GITS was well tolerated by patients with stable symptomatic angina

The Opportunity Cost of the Conservation Reserve Program: A Kansas Land Example

The effects of the Conservation Reserve Program (CRP) on farmland values is investigated using a set of parcel-level data for land sales in Kansas over the period 1998 to 2014. The sales data are used to estimate a hedonic model of land values that allows for the opportunity cost of CRP enrollment to vary across space and time. Factors impacting the opportunity costs include the relative productivity of land, returns to farming, and the time remaining under the CRP contracts. We find that the discount associated with having land under CRP contract averages 7%

Payment Limitations and Acreage Decisions under Risk Aversion: A Simulation Approach

Payment limits have played an important role in U.S. farm policy deliberations for the last thirty years. Current limits are largely nonbinding. Proposals to strengthen and enforce limits are currently in discussion. We evaluate the likely effects of such proposals on acreage for corn, soybeans, wheat, cotton, and rice in several important producing states. Our results generally indicate that payment limits are unlikely to significantly affect acreage in most cases; exceptions occur for cotton and rice, where the probability that limits would be binding is much greater and thus more likely to affect production. Copyright 2009, Oxford University Press.

Predictive value of local and core laboratory echocardiographic assessment of cardiac function in patients with chronic stable angina: The ACTION study

Aims: To evaluate the relationship between echocardiographic cardiac function and outcome in patients with stable symptomatic angina. Methods: Baseline echo left ventricular ejection fraction and volume data measured in a central laboratory was available for 7016 patients (92% of the total) participating in the ACTION trial (A Coronary disease Trial Investigating Outcome with Nifedipine GITS). Ejection fraction was also measured by investigators. Evaluation of the different echocardiographic variables was based on adjusted hazard ratios comparing the unfavourable limit of the 90% range of the variable concerned to the favourable limit. Results: The centrally measured ejection fraction was the most powerful predictor of all-cause death (adjusted hazard ratio = 2.5), myocardial infarction, any stroke or transient ischaemic attack and overt heart failure (adjusted hazard ratio = 4.5). The addition of either end systolic volume or end diastolic volume to ejection fraction did not materially affect the power of prediction. Compared to the central ejection fraction measurement, the investigator-measured ejection fraction was a less powerful predictor for all outcomes considered. Conclusion: Routine echocardiography carefully analysed by standardised methods provides useful prognostic information in patients with stable angina, including for total mortality