Study Rationale Sample Clauses
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 Abaloparatide-SC 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. 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. 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...
Study Rationale. The purpose of this study is to establish safety and efficacy of ALXN2050 in PNH as monotherapy. The C5 inhibitor monoclonal antibody, eculizumab, has been proven effective for the treatment of PNH, resulting in a sustained control of complement-mediated intravascular hemolysis (IVH). Although eculizumab treatment brings patients with PNH a significant clinical benefit, a low-level hemolysis still occurs in many eculizumab-treated patients, leaving approximately one-third of treated patients transfusion-dependent. The blockade of the complement cascade at C5 by eculizumab allows complement component 3 (C3) fragment deposition to proceed without hemolysis on PNH RBCs during C5 inhibitor treatment and is a likely cause for suboptimal response in the subset of patients with PNH who experience extravascular clearance of PNH RBCs coated by C3 fragments (Risitano, 2009). By inhibiting the cleavage of FB, danicopan, the first-generation FD inhibitor, targets the control point for the amplification loop of the complement cascade, blocking C3 convertase formation and, therefore, significantly reduces the production of C3 cleavage fragments and downstream membrane attack complex (MAC) formation ex vivo (Xxxx, 2017). In addition, although FD inhibition does not inhibit components specific to the classical or lectin complement pathways, nor does it inhibit components of the terminal complement pathway, it will inhibit the AP-mediated amplification of complement activity initiated via the classical and lectin pathways. By inhibiting FD with xxxxxxxxx, both IVH, mediated by the activation of the complement terminal pathway, and extravascular hemolysis (EVH), mediated by C3 fragment opsonization in eculizumab-treated patients, can be blocked or significantly attenuated. Xxxxxxxxx has been studied in patients with PNH as monotherapy (Study ACH471-100) with proof of concept established as evidenced by improvement in Hgb and decrease in LDH. Xxxxxxxxx has also been studied in patients with PNH on background therapy with a C5 inhibitor, with proof of concept established (Study ACH471-101). Interim results from this study demonstrate clinically significant improvements in Hgb, a dramatic reduction in transfusion needs, and improvements in other clinical parameters of interest in PNH. ALXN2050 is derived through optimization of danicopan for potency and for PK properties. ALXN2050 displays approximately 3-fold greater potency compared to danicopan and is able to achieve sust...
Study Rationale. There is no shortage of studies linking academic outcomes with health-related behaviors. A 2013 systematic review of the literature from 1985 to 2010 identified 122 original research papers that addressed academic outcomes such as grade point average (GPA), letter grades in specific subjects, standardized test scores, grade level retention, years of schooling completed, and high school graduation and their relationships with health-related behaviors. While many of the associations identified in these studies did not indicate causation in either direction, a reciprocal pattern was established that can greatly alter the life trajectory of adolescents [74]. In 2017, an MMWR paper was published by the CDC that examined 30 health- related behaviors and their associations with academic achievement using 2015 Youth Risk Behavior Survey (YRBS) data. The study reported significantly higher prevalence estimates for protective health behaviors (like eating breakfast everyday), and significantly lower prevalence estimates for health related risk behaviors (such as drinking alcohol) among students with higher academic achievement (mostly As, Bs, and Cs) when compared with students with lower academic achievement (mostly Ds and Fs) in 29 of the 30 behaviors. Tobacco use in any form, however, was not assessed in the analysis [81]. While previous studies have established a strong association between cigarette use and low academic achievement as measured through GPA, standardized test scores, grade level retention, and education level attainment, very little has been published on electronic nicotine delivery systems (ENDS) use and academic achievement suggesting a gap in the literature [74] [50]. The merit in addressing this gap lies not only in the significance of low academic achievement on adolescents’ future life trajectory, but also in the profound effect of ENDS use on adolescents’ current and future health. As the vast majority of tobacco usage is initiated in adolescents, the time an adolescent spends in high school is a crucial time for tobacco prevention [7]. While two studies have been conducted looking at the association between ENDS use and academic achievement using MTF and PATH study data, none to date have stratified by gender, been published using YRBS data, or data that was collected after 2014 [47, 51]. Due to the change in adolescent ENDS use prevalence every year, there is a need to understand whether ENDS use, like many other health-related behaviors,...
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-
Study Rationale. RIST4721 is a small-molecule high-potency antagonist of human CXCR2 that is proposed to have potential as a novel oral treatment for neutrophil-mediated inflammatory diseases, including HS. HS is a chronic, inflammatory skin disease characterized by recurrent painful nodules and abscesses that rupture, leading to the formation of sinus tracts and scarring. Recruitment of neutrophils to HS lesion sites may play an essential role in the development of the painful inflammatory nodules and abscesses that characterize the disease (Xxxxx, 2021). CXCR2 is a GPCR expressed on the epithelium and on a variety of inflammatory cells (including neutrophils and macrophages). It plays important roles in various acute and chronic inflammatory processes (Xxxxxxxx, 2012; Xxxx, 2017). CXCR2 serves as a receptor for a number of cytokines, including IL‑8, and is required for neutrophil egress from the bone marrow and recruitment to distant inflammatory sites (Xxxx, 2010; Xxxxxxx, 2014). Given the role of neutrophils in inflammation, the blockade of CXCR2 may represent a novel therapeutic approach for the treatment of neutrophil‑mediated inflammatory disorders, such as HS (Xxxxxxx, 2014; Aarts, 2021). RIST4721 antagonism of CXCR2 was demonstrated in vitro by measuring both primary binding affinity in HEK293 cells transfected with recombinant CXCR2 (whole cells and membranes) and functional end points in isolated peripheral polymorphonuclear cells and human blood neutrophils. In in vitro pharmacology studies covering a number of related receptors and targets inhibited by structurally similar molecules, RIST4721 demonstrated a CXCR2 selectivity of 134-fold and 47-fold relative to its potency at the human CXCR1 and CCR2, respectively (Nicholls, 2015). The in vitro evaluation of RIST4721 as a high-potency CXCR2 antagonist translated well in vivo in 4 studies with a rat air pouch model of MSU crystal-induced inflammation. When rats were previously challenged with MSU injection, RIST4721 caused significant, dose-dependent decreases in exudate volume, total WBC count, and neutrophil infiltration at doses 30, 100, and 300 μmol/kg. RIST4721 was evaluated in 5 Phase 1 clinical studies in healthy subjects and is also being evaluated in clinical setting for treatment of PPP and FMF. RIST4721 was generally well tolerated in completed clinical studies. The present study will evaluate the safety, tolerability, and efficacy of RIST4721 monotherapy in subjects with moderate-to-severe HS.
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. This study is designed to specifically target subjects with PED secondary to neovascular macular degeneration. This study will aim to describe the effects of brolucizumab on baseline PED status and height as well as visual and anatomic outcomes in patients with neovascular AMD treated with brolucizumab on a fixed dosing regimen according to the product label. Brolucizumab is an inhibitor of VEGF with a mechanism of action similar to ranibizumab but with a smaller molecular size (26 kDa and 48 kDa respectively). Nonclinical studies have demonstrated that RTH258 is at least as potent as ranibizumab, with a similar vitreal half-life and a significantly lower systemic exposure. The low systemic exposure should confer a good safety profile even at a high dose. The higher dose, similar half-life, and potency of RTH258 may confer a longer treatment duration compared to currently available treatments. Two clinical studies, C-10-083 and C-12-006, have demonstrated that RTH258 is as effective as ranibizumab and aflibercept in improving BCVA outcomes whilst having a reduced treatment frequency, thus providing a potential benefit to patients and their caregivers/physicians. The ocular and systemic safety profile of single or repeated doses of RTH258 were also evaluated in the C-10-083 and C-12-006 studies, respectively, and demonstrated similar safety profiles to ranibizumab and aflibercept. Further details of the known and potential risks and benefits associated with RTH258 are presented in the Investigator’s Brochure. Summarized, the results from the Phase 2 studies demonstrate that brolucizumab has similar efficacy to currently available treatment options with potentially greater duration. These data support the further development of RTH258 with a treatment regimen including q12 maintenance dosing.