Reviews on Recent Clinical Trials - Volume 6, Issue 2, 2011

Cystic fibrosis (CF) is an autosomal recessive disorder characterized by chronic lung and sinus disease, impaired mucociliary clearance (leading to recurrent pulmonary infection), pancreatic insufficiency, elevated sweat chloride levels and male infertility. Cystic fibrosis transmembrane conductance regulator (CFTR) is a cAMP-regulated chloride channel in the plasma membrane of epithelial cells lining the lung, pancreas, liver, intestines, sweat duct, and the epididymis. Genetic mutations in CFTR affect its synthesis, processing, and transport to the plasma membrane and/or impede its function as a chloride channel and conductance regulator. Research is proceeding on multiple fronts including inhalational agents, anti-inflammatory treatments, and pancreatic replacement therapies. Furthermore, improved understanding of the molecular mechanisms that lead to CFTR dysfunction has stimulated the design of therapeutic strategies aimed at restoration of CFTR function, or “protein repair therapy”. Recent clinical trials have shown these interventions have the ability to restore some level of CFTR function in vivo. This review will provide an overview of recent clinical trials that investigate new therapeutic approaches in CF designed to treat chronic respiratory infection, reduce inflammation, and improve pancreatic enzyme supplementation as well as trials addressing the greatest therapeutic challenge - restoring the function of the CFTR protein.

Lipoprotein-associated Phospholipase A2 (Lp-PLA2) is an enzyme that belongs to the A2 Phospholipase superfamily and is produced by inflammatory cells that are involved in the process of atherogenesis. Even though there is controversy in current bibliography whether Lp-PLA2 exerts proatherogenic or anti-atherogenic properties, the weight of evidence suggests a pro-atherogenic role for this protein. Lp-PLA2 is detected in human atherosclerotic lesions and elevated Lp-PLA2 levels are associated with an increased risk of cardiovascular events and adverse events in patients with coronary artery disease independently of traditional risk factors and other markers of inflammation. It has been recently shown that direct pharmacological inhibition of Lp-PLA2 activity exerts beneficiary effects on the atherosclerotic process. This finding is most interesting since it could offer a novel target for therapeutic intervention in patients suffering from cardiovascular disease. The purpose of this review article is to report on the role of Lp-PLA2 in cardiovascular diseases and to enlighten the putative pathophysiologic mechanisms by which this protein exerts its effect on cardiovascular function. Additionally, the pharmacological interventions that influence Lp-PLA2 activity and may offer a new approach for the treatment of atherosclerosis will be analyzed.

Osteoarthritis (OA) is a chronic arthritis affecting growing numbers of the ageing population. Patients diagnosed with OA place a large burden on access to healthcare services, including primary care, prescription of analgesic drugs, physiotherapy and joint replacement surgery. Not all patients diagnosed with OA will require joint replacement surgery, and therefore avenues for non-surgical treatment for such patients need be explored in many cases. In this review we discuss current concepts underlying the pathophysiology of OA. These form a basis to understanding the rationale for new and existing therapies based on recent evidence available from clinical studies and trials in OA. In particular, we discuss the evidence for use of pharmacological treatments, including NSAIDs (non-steroidal anti-inflammatory drugs), chondroitin sulphate and glucosamine, hyaluronan, potential disease-modifying drugs and other interventions such as weight reduction and physiotherapy. Finally, we discuss new developments from clinical evidence for surgical options, including ACL repair surgery and joint replacement surgery.

Surgery remains the mainstay of melanoma therapy at all sites. Melanoma is widely believed to be a radioresistant tumor, a misconception that has historically led to the limited use of RT for its treatment. We searched pubmed from 1978 until 2010 by means of prospective randomized trials. The aim was to assess the potential impact of radiotherapy (RT) on local control, quality of life and overall survival. Radiotherapy should be considered in lentigo maligna, especially in elderly patients with extensive or unresectable disease in difficult areas on the face, with adequate tumor control with good cosmetic and functional results. In addition, radiation therapy provides effective palliation in patients with metastatic malignant melanoma. Doses up to 30 Gy or BED > 39.0Gy were found to be associated with prolonged palliation. These findings should be viewed with caution because the lack of data regarding performance status as well as other unknown confounding factors limits the applicability of retrospectives studies. We recommend that higher doses of RT be considered when using RT for the palliation of patients with metastatic melanoma and a performance status that could tolerate such therapy. In the futute, the combination of radiation therapy with hyperthermia may be a reasonable therapeutic option.

An incomplete inhibition of the renin angiotensin aldosterone system (RAAS) may be responsible for the residual organ damage and event rate that still occur in spite of an apparent blood pressure control in patients with hypertension, diabetes, chronic kidney disease and heart failure treated with angiotensin converting enzyme inhibitors (ACEI) or angiotensin receptor blockers (ARB). Additional antiproteinuric effect in diabetic and non diabetic chronic kidney disease, and reduction in hospitalizations in patients with heart failure already receiving a single RAAS antagonist, has been achieved by incremental inhibition of the RAAS with dual therapy or uptitration of an individual agent above conventional dosages. However, the synergistic increase in plasma renin activity (PRA) and the angiotensin II escape could reduce the expected benefit obtained with dual therapy. Results from ONTARGET showing a lack of additional outcome benefit over monotherapy, with a concomitant increase risk of hyperkalemia, renal impairment, and hypotension, discourage the use of the ACEI/ARB combination in patients at high risk of cardiovascular events. This occured despite a lower albumin excretion in dual versus single RAAS blockade, indicating that an incremental antiproteinuric effect is not automatically translated into clinical outcome benefit. The efficacy and safety of ACEI/ARB combination versus monotherapy in patients with overt proteinuria is currently evaluated by LIRICO and VA NEPHRON-D clinical trials. The long lasting direct renin inhibitor aliskiren, acting at the first and rate limiting step of the RAAS cascade, prevents the reactive increase in PRA when combined with ACEIs, ARBs or diuretics. The ASPIRE HIGHER programme, involving more than 35,000 patients with hypertension, heart failure, kidney disease and diabetes, is currently evaluating the efficacy and safety of aliskiren on top of standard therapy. The clinical benefit of adding mineralocorticoid receptor blockers (MRBs) in the control of resistant hypertension, proteinuric kidney diseases, and prevention of mortality in patients with heart failure on top of conventional treatment, evidences the pathogenic role of inadequately suppressed aldosterone as a cause of suboptimal response to conventional RAAS inhibition. The present review will focus on the pathophysiological ground, and the evidence provided by clinical trials assessing the efficacy and safety of recent strategies for the prevention of cardiovascular events and target organ damage progression via enhanced RAAS inhibition.

As coronary artery disease (CAD) remains a leading cause of death in the world, the development of anticoagulants to prevent CAD progressing to myocardial infarction and death is a high priority. A number of direct Factor Xa (FXa) inhibitors are being developed for use in CAD. Despite being developed to the stage of Phase II clinical trials, DX- 9065a is no longer a priority with its developing company for further development, possibly because the Phase II trials did not show any major benefit of DX-9065a over heparin in subjects undergoing percutaneous coronary interventions (PCI) or with non-ST-elevation acute coronary syndromes (ACS). ZK-807834, otamixaban, apixaban, and rivaroxaban are all direct FXa inhibitors that have undergone preclinical and some clinical testing for use in CAD. In a large Phase II clinical trial of subjects with ACS, some doses of otamixaban had a better benefit/risk profile than the unfractionated heparin/ eptifibatide combination. However, neither ZK-807834 nor otamixaban appear to be undergoing further clinical development at present. In ACS, placebo-controlled large Phase II clinical trials with apixaban and rivaroxaban have not shown clear cut benefits. Nevertheless, apixaban and rivaroxaban are presently in placebo-controlled Phase III clinical trials for ACS. Presently, there is no compelling evidence to support the use of direct FXa inhibitors in ACS.

Meta-analytic reviews of Randomized Clinical Trials (RCT) have reached contradictory conclusions regarding the benefit of medical interventions in Advanced Colorectal Cancer (ACRC). Surrogate markers of survival benefit, such as response rate (RR) and progression free-survival (PFS) often show contradictory and highly variable correlations [1-6]. These contradictions can be due to differences in 1) the studies analysed (sources), 2) the quality of clinical trials (intrinsic bias in the design, biased data analysis, heterogeneous PFS definitions) and 3) the second-line strategies between arms. PFS is a more vulnerable target than overall survival (OS), but the latter can also be affected by different biases and additional medical interventions such as secondary resection of metastases or second-line therapies. Therefore the correlation between PFS and survival must be clearly stated if PFS is to be considered as a primary endpoint. Of the differences between studies, only the quality of clinical trials can be improved by a deeper knowledge of both the area of study (i.e. colorectal cancer) and the methodology needed (i.e., clinical and translational trials). The aim of this manuscript is to offer the basic resources to develop experimental trials in ACRC. To this end, techniques for diagnosis and for response assessment are discussed, prognostic factors and treatment standards are critically exposed, and notes about how to design useful translational studies are provided.

As a result of widespread serum prostate-specific antigen (PSA) screening and prostate cancer awareness, the detection of low-grade prostate cancer has increased. At the moment, it is unclear how to treat patients in this population. Thus, we focused on reviewing therapies for patients in this low risk group. The purpose of this review paper is to present the status of emerging therapies of cryotherapy and high-intensity focused ultrasound (HIFU) in patients with low risk disease. Based on our review of the literature, there are several small-scale studies of these two therapies that have revealed favorable outcomes, but with complications of urinary incontinence and impotence. With further research, these therapies may develop into good alternatives for patients in this expanding group.

Tolvaptan is a new agent in the treatment of normovolemic and hypervolemic hyponatremia. It is a V2 receptor antagonist inducing free water diuresis. It has been recently approved in USA and Europe for the treatment of hyponatremia associated with SIADH, cirrhosis as well as heart failure, while in hypovolemic hyponatremia its use is contraindicated. The drug also appears to be effective in the acute exacerbations of heart failure that need hospitalization. In the short-term tolvaptan seems to relieve acute congestive symptoms and improves mortality. However, the long-term effects on mortality are still controversial. The favorable short-term effects are ascribed to the selective V2 receptor blocking, while the unopposed stimulation of V1A may give an explanation for the lack of long-term benefit. The drug should be initiated in the hospital setting because careful monitoring of fluid balance is recommended. It is administered orally giving the advantage of continuation in the outpatient setting. Moreover tolvaptan may have a role in the treatment of autosomal dominant polycystic kidney disease (ADPKD). Its effectiveness has been shown in animal models and Phase 3 clinical trial as well as an open-label study is now active. Since tolvaptan is metabolized by the cytochrome CYP3A4 in the liver physicians should be aware of possible drug to drug interactions. Resulting from large studies tolvaptan appears well tolerated. Common side effects are thirst, dry mouth and polyuria. Tolvaptan opens a new page not only in the treatment of normovolemic and hypervolemic hyponatremia but also in the treatment of acute decompensated heart failure and probably in ADPKD.