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. 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 [Xxxxxx, 1997] 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 [Xxxxx, 2000] suggests 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 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 † SERETIDE, XXXXX, ADVAIR, DISKUS and ACCUHALER are Trade Marks of GlaxoSmithKline group of companies. Registered in US Patent and Trademark Office. bronchodilators, and long term oral corticosteroids), in moderate to severe COPD subjects w...
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. 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. Trichomoniasis is the most prevalent nonviral sexually transmitted infection in the United States, affecting an estimated 3.7 million persons (Xxxxxxxxxxx 2013); Lupin is developing Solosec as an available treatment option to provide an alternative, effective, single dose therapy for women diagnosed with trichomoniasis that, in turn, should decrease the known serious sequelae that occur when this infection is left untreated or ineffectively treated. Drugs of the 5-nitroimidazole family are the only known medications to be effective against trichomoniasis (CDC 2015). Metronidazole, tinidazole, and secnidazole are reported to have about approximately 90-95% success rate in curing T. vaginalis (Xxxxxxx 2004, Forna 2003, Xxxxx 1980, Manorama 1978, Xxxxx 2015) depending on study design. Members of the 5-nitroimidazole family vary in half-life, Cmax, and side effects. Secnidazole has been widely used outside the U.S. for many years. CDC currently recommends metronidazole 2 g orally in a single dose or tinidazole 2 g orally in a single dose (CDC 2015); metronidazole 500 mg BID for 7 days is recommended as the alternative treatment regimen. Since cure rates with Solosec are anticipated to be high, this trial was designed to avoid the possibility of unprotected sex resulting in reinfection which becomes more likely the longer the interval between treatment and TOC. Peterman et. al. found a reinfection rate of 16.5% among women initially diagnosed and treated for T. vaginalis at baseline (Xxxxxxxx 2006). In light of these data on clearance and chance for re-infection, a window for the TOC visit to be 6-12 days was selected. Since it is possible that this timing will create false positive NAAT (TMA) results and since reinfection in this group of women at high risk for STD is of greater importance to assess the efficacy of Solosec, trichomonas culture was selected as the criterion for cure.
Study Rationale. This study will evaluate the efficacy and safety of vibegron, a beta-3 adrenergic receptor (β3-AR) agonist, in the treatment of pain associated with irritable bowel syndrome (IBS) that is associated with predominantly diarrhea (IBS-D) or has mixed episodes of diarrhea and constipation (IBS-M). The rationale for the study is based on both animal models of functional gastrointestinal disorders and Phase 1 and Phase 2 clinical studies of the β3-AR agonist solabegron. Animal models have shown that β3-AR activation can protect against gastric ulcers, inhibit castor-oil induced diarrhea, and reduce observed pain behavior [Vasina, 2008; Xxxxxx, 2007]. The clinical studies of solabegron have shown improvement in pain among women with IBS, with no effect on gut motility in healthy subjects [Grudell, 2008; Xxxxxxxx, 2008]. Although this is the first study of vibegron in the setting of IBS, vibegron has been studied in the overactive bladder population (including a completed large Phase 2b dose-ranging study, 2 completed Phase 3 studies in Japan, and 2 ongoing global Phase 3 studies), and all clinical data available to date indicate that vibegron has been well tolerated.
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 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...
