Study Rationale. The purpose of the study is to provide longer term safety data, fracture data and BMD data after six months of treatment with alendronate, in otherwise healthy ambulatory postmenopausal women with severe osteoporosis who have previously received 18 months of blinded treatment with BA058 Injection or Placebo. Following the initial six months of treatment in this study, subjects will enter the long-term observational phase of the study during which the subjects will continue to receive alendronate for an additional 18 months.
Study Rationale. This study is designed as a randomized, double-blind, placebo-controlled, comparative Phase 3 study of BA058 in the treatment of postmenopausal women with severe osteoporosis and at risk of fracture. The purpose of the study is to evaluate the efficacy and safety of BA058 80 µg in the prevention of fracture in otherwise healthy ambulatory postmenopausal women with severe osteoporosis. The dose chosen for this study is based on the safety and pharmacodynamic information derived in study BA058-05-002 according to predetermined criteria provided in the protocol. The population to be studied is the recommended and intended population for treatment, postmenopausal women with severe osteoporosis (17-19). Daily SC doses of BA058 80 µg, Placebo or teriparatide 20 µg will be self-administered for 18 months (78 weeks) to patients randomized [equally] to one of 3 treatment groups.
Study Rationale. Accurate measurements of intracellular cystine content are mandatory for the diagnosis and for the monitoring of the effects of cysteamine treatment. There are two components to the measurement, that for cystine content, and that for indexing the cystine content to the protein level of the cells in which it is measured. Several methods have been developed to measure cystine content in leucocytes. They differ according to the type of cells used. Historically, cystine has been measured in mixed leucocyte preparations, despite the fact that it accumulates preferentially in polymorphonuclear granulocytes (PMNC). Normal subjects have PMNC cystine levels lower than 0.25 nmol ½ cystine/mg protein. The diagnosis of cystinosis is confirmed when the PMNC cystine levels are > 2 nmol ½ cystine/mg protein. Cystinosis is treated specifically using cysteamine to reduce intracellular cystine levels. Following early publications (Xxxxxx, Xxxxxx et al. 1976), it was thought that the PMNC cystine level should be maintained lower than 2 nmol ½ cystine/mg protein for the treatment of cystinosis with cysteamine to be effective. For patients treated with Cystagon®, leukocyte cystine measurements are useful to determine appropriate dosage and drug adherence. “When measured 5 to 6 hours after Cystagon® administration, the goal should be a level < 1 nmol ½ cystine/mg protein. In some patients with poorer tolerability for Cystagon®, patients may still receive benefit with a white blood cell cystine level of less than 2 nmol ½ cystine/mg protein” (Cystagon® Package Insert, 2007). Variability exists in the measured cystine content in cells. Some of the variability arises from the types of cells harvested for the measurement. An even greater source of variation of the cystine level stems from the method used to determine the amount of protein used to normalize the result of the cystine assay with respect to total amount of protein in the cells. Although there is no explicit reference in the Cystagon® Package Insert as to which protein assay should be used to determine that the cystine level is less than 1 nmol ½ cystine/mg protein, the first laboratories known for measuring WBC cystine, have used the Xxxxx assay, which makes the Xxxxx assay as the method of reference, by default. The methods for the analysis of cystine and cellular total protein in white blood cells (WBC) for the current study were validated at West Lafayette, IN under GLP principles (good laboratory practice or GLP sp...
Study Rationale. COPD is a disease with rising morbidity and mortality. The recent Global Burden of Disease Study (31) ranks COPD as the 6th leading cause of mortality and the 12th leading cause of morbidity (defined as disability-adjusted life years (DALYs)) world-wide. These figures are expected to rise, with COPD becoming the 3rd leading cause of mortality and the 5th leading cause of morbidity by the year 2020. Furthermore, trends in the use of medical care resources indicate that the economic cost of COPD continues to rise in direct relation to the ageing population, the increase in prevalence of disease, and the cost of new and existing medical and public health interventions (Xxxxx S; ERS 1999). The largest share of medical care costs for COPD is a consequence of an acute exacerbation resulting in hospitalisation. COPD exacerbations have also been associated with decrements in pulmonary function, and contribute substantially to the reduced quality of life in patients with the disease. In much of the world, the full effect of existing smoking patterns has not been seen so that COPD mortality is rising. Post-hoc analysis of data from ISOLDE suggest a reduced mortality rate in COPD subjects randomised to FP compared with placebo, during the 3 years post-randomisation. Although XXXXXX was not designed to investigate mortality, and therefore the study should be regarded as a pilot, the data provide a rationale on which to base a definitive mortality study. No prospective mortality data are available for subjects treated with salmeterol. However, it can be hypothesised that the properties of salmeterol, particularly its cytoprotective effects and hence its potential to reduce infective exacerbations, could have a significant impact on subject survival. If this is the case, there could be, at least, an additive effect of salmeterol and FP in reducing mortality in subjects with COPD. The purpose of the present study is to determine the effects on mortality and morbidity of the salmeterol/FP combination product (SERETIDE†) at a dose of 50/500µg bd † DISKUS and SERETIDE are Trade Marks of GlaxoSmithKline group of companies. Registered in US Patent and Trademark Office. compared with each component alone and with placebo, when added to usual COPD therapy (defined as any treatment but excluding inhaled corticosteroids, inhaled long- acting bronchodilators, and long term oral corticosteroids), in moderate to severe COPD subjects with poorly reversible airflow obstruction.
Study Rationale. Most advanced cancers eventually become refractory to conventional therapies and new treatment modalities are needed. Immunotherapy, which is based on the enhancement of an immune response against the tumor, is a promising approach to treating many cancer types. T cells play an important role in destroying diseased cells throughout the body. Studies with immune checkpoint inhibitors and tumor infiltrating lymphocytes have demonstrated the potential of T cells to treat cancer. T cells need to possess the appropriate specificity for a tumor, be present in sufficient numbers, and overcome any local immunosuppressive factors to be effective. Engineered T cells are a promising approach for cancer therapy (Xxxxxxx et al, 2013). Engineered Autologous Cell Therapy (eACT™) is a process by which a patient’s own T cells are collected and subsequently genetically altered to recognize and target antigens expressed on the cell surface of specific malignancies (Xxxxxxxxxxxx et al, 2013). The ability to genetically engineer human T cells and use them to mediate cancer regression in patients has been demonstrated in a number of studies (Xxxxxx et al, 2014; Xxxxx et al, 2014; Xxx et al, 2015) and has opened possibilities for the treatment of patients with a wide variety of cancer types including B-cell malignancies expressing the CD19 antigen. Given the poor outcomes which have been achieved to date in adults with r/r ALL (Table 1), this trial will enroll adult subjects with r/r B-precursor ALL as evidenced by failure to achieve or maintain a response to prior systemic therapy, or by recurrence after allogeneic SCT. Patients with T-cell lineage ALL will not be enrolled since their malignancies are CD19- and will likely not respond to a CD19 directed agent.
Study Rationale. During the last years, growing evidence of the pivotal role of IFNγ in the development of HLH has been demonstrated7;14;15;24-26. The mutations of genes which characterize primary forms of HLH all affect proteins involved in the same process, ultimately impairing cytotoxic activity. Perforin mutations were the first identified in HLH patients. Xxxxxxxx knocked out (KO) mice are considered a relevant model for the human disease. In fact, these mice, once infected with LCMV, develop all the diagnostic and many of the clinical and laboratory characteristic features of the human disease, and they die if untreated. For these reasons, perforin KO mice have been used to study the pathophysiology of HLH. The HLH-like pathology that they develop is dependent on CD8+ T cells and IFNγ produced in response to antigen stimulation. It was demonstrated that when the high circulating levels of IFNγ are neutralized, with the administration of an anti-IFNγ antibody, not only are the clinical and laboratory abnormalities reverted, but also survival rate is dramatically improved. On the contrary, the ablation of any other cytokine had no impact on survival14;15. Two models of secondary HLH have been investigated in the context of the NI-0501 development program. In one model, repeated administration of CpG (causing TLR9 stimulation) has been used to mimic a chronic severe hyperstimulation in healthy mice (i.e. with normal genetics of the cytotoxic pathway) as a model of HLH secondary to infection. Although these mice do not necessarily die, they develop typical clinical and laboratory features of HLH. When IFNγ is neutralized, with the administration of an anti-IFNγ antibody, clinical and laboratory features of the disease are reverted. Interestingly, in this model it has been demonstrated that administration of the anti-IFNγ antibody leads to full neutralization of IFNγ effects also in relevant target tissues, such as liver and spleen (manuscript in preparation). To study the physiopathology of secondary HLH occurring in the context of rheumatic diseases, an animal model has been generated using IL-6 transgenic mice expressing high levels of IL-6, similarly to what occurs in patients with sJIA, the rheumatic disease most frequently associated with secondary forms of HLH. When triggered with Toll Like Receptor (TLR) ligands, these mice die with many of the features of the human disease27. In these mice, when IFNγ is neutralized with the administration of an anti-IFNγ antibody...
Study Rationale. KPL-716 is a first-in-class, fully-human monoclonal antibody against Oncostatin M Receptor beta (OSMRβ). OSMRβ is a cell surface receptor that heterodimerizes with IL-31 receptor alpha (IL-31Rα) to mediate signaling of IL-31. It also heterodimerizes with gp130 to mediate signaling of oncostatin (OSM). By targeting a single epitope , KPL-716 simultaneously inhibits signaling of IL-31 and OSM, two (2) cytokine pathways important in pruritus, inflammation, hyperkeratosis and fibrosis. KPL-716 does not inhibit signaling of OSM down the Leukemia Inhibitory Factor Receptor (LIFR) pathway, a pathway implicated in hematopoiesis and platelet synthesis.21 KPL-716 via its dual pathway mechanism is predicted to reduce pruritus in chronic pruritic diseases and potentially modulate many aspects of disease pathology related to inflammation, hyperkeratosis and fibrosis. A clinical effect on pruritus intensity is anticipated at therapeutic doses based on the Phase 1b study results (Protocol KPL-716-C001). The targeted nature of the KPL-716 mechanism of action is expected to offer safety advantages compared to immunosuppressive therapies as well as systemic and topical corticosteroids. The role of IL-31 in pruritus is well established, as IL-31 receptor inhibition has been shown to decrease pruritus in subjects with atopic dermatitis.22, 23 The published literature suggests that IL-31 plays a role in many chronic pruritic diseases. Serum IL-31 levels are elevated in CIU patients compared to healthy controls and IL-31 levels decrease upon successful treatment of CIU.24 Similarly, serum IL-31 levels are increased in patients with psoriasis and levels decrease after UVB irradiation with treatment response.25 IL-31 levels are also elevated in patients with LP although pruritus intensity does not appear to correlate with IL- 31 levels in this disease.15 Despite absence of a primary dermatologic process in CIP, histologic analysis of CIP skin demonstrates lymphocytic and, in many cases, eosinophilic infiltration, accompanied by increased IgE and peripheral blood eosinophilia pointing to TH2 polarization as a potential source of IL-31.3 Chronic scratching, disruption of epidermal barrier function, staphylococcal colonization and subsequent staphylococcal enterotoxin B production promote IL-31 production26 and may ultimately contribute to the itch-scratch cycle that underlies many chronic pruritic diseases such as atopic dermatitis and LSC. OSM, the other cytokine pathway inhibited...
Study Rationale. Most anti-arrhythmic agents currently approved for the treatment of atrial fibrillation (AF) are either contraindicated or have label warnings for use in heart failure patients due to an increased risk of mortality in this patient population. Bucindolol hydrochloride (bucindolol) is a nonselective ß-adrenergic receptor (ß-AR) blocking agent with mild vasodilator properties, which was previously studied in the BEST Phase 3 heart failure trial. In a large pharmacogenomic substudy of the BEST trial, two unique pharmacologic properties of bucindolol, sympatholysis and inverse agonism, were shown to interact with adrenergic receptor polymorphisms in such a way that targeting specific genotypes of these variants could improve therapeutic index. Specifically, patients with the ß1389Arg/Arg AR variant had more efficacious treatment responses to bucindolol, as assessed by HF clinical outcomes and the reduction of new onset AF, compared to patients with the ß1389 Gly polymorphism (i.e., Gly carriers). Metoprolol succinate (metoprolol CR/XL) is a ß1-adrenergic receptor (AR) selective beta blocker indicated for the treatment of stable, symptomatic (NYHA Class II or III) heart failure of ischemic or nonischemic origin. Metoprolol has demonstrated mild efficacy for the prevention of new onset AF in a heart failure patient population and is often used off-label in this setting (Class IIa indication with a “C” level of evidence for AF prevention per ACC/AHA/ESC joint Guidelines). In a previous study, metoprolol decreased the incidence of AF recurrence, compared to placebo, in patients with persistent AF who had recently undergone electrical cardioversion (ECV) to sinus rhythm. In contrast to bucindolol, metoprolol CR/XL does not appear to confer added clinical benefits in patients that possess the ß1389Arg/Arg AR variant. The goal of the GENETIC-AF trial is to demonstrate the superiority of pharmacogenetically targeted bucindolol compared to metoprolol therapy for the prevention of symptomatic AF in a genotype-defined ß1389Arg/Arg heart failure population with persistent AF that has recently undergone cardioversion to sinus rhythm. The trial utilizes an adaptive design, with initial enrollment of 200 patients who will have their rhythm continuously monitored through inserted or implanted devices to measure XX xxxxxx (AFB) in addition to the other study endpoints. If the independent Data Safety Monitoring Committee (DSMB) determines that an efficacy signal favorable to buc...
Study Rationale. Nitrogen Dioxide: simply a marker of traffic and air pollution or a significant respiratory health threat on its own right? Air pollution is obviously a fundamental problem; it can affect all facets of life from the environment and politics to health and life expectancy [272]. Therefore, the role of regulating bodies such as the European Commission that set the permissible levels for the different air pollutants is of imperative importance. However, setting effective regulations that will protect the public implies an excellent understanding of the toxicity and pathophysiological actions of the different air pollutants. Such an understanding has not been reached for NO2 and this is the basis of the current PhD project. Specifically, there are three major air pollutants that warrant consideration from a public health viewpoint; O3, PM and NO2. Studies examining the respiratory effects of O3 have shown that it can affect lung function and cause respiratory symptoms [73]. In addition studies have demonstrated that PM –a diverse suspension of fine liquid and/or liquid particles - can have significant negative respiratory effects [273] although its effects depend on its composition which is characterized by seasonal and temporal variation [274]. The toxicological information on NO2 is far more limited while the existing studies do not offer tangible information on its toxicity and mechanisms of action. As presented in the literature review above, there are questions over the chosen concentrations for both the animal and in vitro studies while the epidemiological studies offer tentative conclusions. Given that the levels of NO2 and the other air pollutants are highly correlated a key issue is how can we possibly ascertain that the effects observed in the epidemiological studies are due to the actions of NO2 per se? One can possibly argue that NO2 is acting as a surrogate. At the same time, one cannot exclude the possibility that unexplored additive effects are taking place. Thus, the three major air pollutants need to be tested within the same experimental system in order to collect reliable data on the relative toxicity of NO2 and this is precisely the aim of the current PhD project. During this project the aforementioned air pollutants were tested within the same experimental set up, while also concomitant exposures were considered. The respiratory tract lining fluid (RTLF) was modelled given the fact that it is the first physical interface that the air pollut...
Study Rationale. Patients with advanced/metastatic CRC (mCRC) are typically treated with 5-FU and oxaliplatin or irinotecan-based regimens in first- and second-line disease management. Treatment selection depends on clinical factors and molecular markers. Despite initial response rates around 60% with first line chemotherapy, mCRC remains incurable. After progression free survival (PFS) of about 8-12 months, the disease recurs with and overall survival (OS) remains poor around 30 months (Xxxxx 2008; Xxxxxxxxx 2010; Loupakis 2014; Xxx Xxxxxx 2011; Venook 2017). Second line chemotherapy in recurrent mCRC yields considerably less efficacy with response rates of 5- 36%, PFS lasing 5-7 months, and OS of 11-14 months (Xxxxxxxxx 2007; Bennouna 2013; Sobrero 2008; Peeters 2014). The options for the third line therapy of mCRC are very limited. Additionally, patients who have RAS-mutated CRC lack effective therapies and are treated with agents that demonstrate only modest survival gains. Response rate and survival in patients with mutations in RAS proteins remains an unmet medical need due to the poor antitumor responses, few treatment options, and the aggressive nature of the tumors leading to a shorter survival. Currently regorafenib and combination of trifluridine and tipiracil are third and later lines treatments for patients with mCRC including those with RAS mutations. Immune checkpoint inhibitors are approved for approximately 5% of CRC patients with MSI-H/dMMR tumors. Anti- EGFR targeted therapies, cetuximab and panitumumab, are only indicated for EGFR-expressing KRAS wild-type mCRC in the EU per SmPC. Pembrolizumab, an anti-PD-1 mAb, is approved as the first-line treatment of patients with unresectable or metastatic microsatellite instability- high (MSI-H) or deficient mismatch repair (dMMR) colorectal cancer. In a study of pembrolizumab in CRC, regardless of MSI status but with PD-L1-positive disease, the XXX was only 4% (1 out of 23 enrolled and treated). In a review of the patient with a tumor response, it was noted that patient who responded was the only one with MSI-H disease. In the study KEYNOTE-016, patients with microsatellite stable (MSS) disease had an XXX of 0% (95% CI: 0, 20), while those patients with mismatch repair–deficient colorectal adenocarcinomas had an XXX of 40% (95% confidence interval [CI], 12, 74) (Li 2015). Further studies using pembrolizumab have limited the population to MSI-H only; the population for which pembrolizumab received approval. Resul...
