An update on emerging drugs in osteosarcoma: towards tailored therapies?

ABSTRACT

Introduction: Current treatment of conventional and non-conventional high-grade osteosarcoma (HGOS) is based on the surgical removal of primary tumor and, when possible, of metastases and local reccurrence, together with systemic pre- and post-operative chemotherapy with drugs that have been used since decades.

Areas covered: This review is intended to summarize the new agents and therapeutic strategies that are under clinical evaluation in HGOS, with the aim to increase the cure probability of this highly malignant bone tumor, which has not significantly improved during the last 30–40 years. The list of drugs, compounds and treatment modalities presented and discussed here has been generated by considering only those that are included in presently ongoing and recruiting clinical trials, or which have been completed in the last 2 years with reported results, on the basis of the information obtained from different and continuously updated databases.

Expert opinion: Despite HGOS is a rare tumor, several clinical trials are presently evaluating different treatment strategies, which may hopefully positively impact on the outcome of patients who experience unfavorable prognosis when treated with conventional therapies.

Trial registration: ClinicalTrials.gov identifier: NCT01459484.

Trial registration: ClinicalTrials.gov identifier: NCT01669369.

Trial registration: ClinicalTrials.gov identifier: NCT00134030.

Trial registration: ClinicalTrials.gov identifier: NCT00180908.

Trial registration: ClinicalTrials.gov identifier: NCT00470223.

Trial registration: ClinicalTrials.gov identifier: NCT01532687.

Trial registration: ClinicalTrials.gov identifier: NCT02357810.

Trial registration: ClinicalTrials.gov identifier: NCT03163381.

Trial registration: ClinicalTrials.gov identifier: NCT02432274.

Trial registration: ClinicalTrials.gov identifier: NCT02048371.

Trial registration: ClinicalTrials.gov identifier: NCT02389244.

Trial registration: ClinicalTrials.gov identifier: NCT02243605.

Trial registration: ClinicalTrials.gov identifier: NCT02867592.

Trial registration: ClinicalTrials.gov identifier: NCT03210714.

Trial registration: ClinicalTrials.gov identifier: NCT03526250.

Trial registration: ClinicalTrials.gov identifier: NCT03213678.

Trial registration: ClinicalTrials.gov identifier: NCT03718091.

Trial registration: ClinicalTrials.gov identifier: NCT03233204.

Trial registration: ClinicalTrials.gov identifier: NCT03698994.

Trial registration: ClinicalTrials.gov identifier: NCT03220035.

Trial registration: ClinicalTrials.gov identifier: NCT03220035.

Trial registration: ClinicalTrials.gov identifier: NCT02689336.

Trial registration: ClinicalTrials.gov identifier: NCT03678883.

Trial registration: ClinicalTrials.gov identifier: NCT01962103.

Trial registration: ClinicalTrials.gov identifier: NCT02945800.

Trial registration: ClinicalTrials.gov identifier: NCT01669369.

Trial registration: ClinicalTrials.gov identifier: NCT03598595.

Trial registration: ClinicalTrials.gov identifier: NCT02644460.

Trial registration: ClinicalTrials.gov identifier: NCT02517918.

Trial registration: ClinicalTrials.gov identifier: NCT03002805.

Trial registration: ClinicalTrials.gov identifier: NCT02013336.

Trial registration: ClinicalTrials.gov identifier: NCT02536183.

Trial registration: ClinicalTrials.gov identifier: NCT02557854.

Trial registration: ClinicalTrials.gov identifier: NCT02390843.

Trial registration: ClinicalTrials.gov identifier: NCT03643133.

Trial registration: ClinicalTrials.gov identifier: NCT03006848.

Trial registration: ClinicalTrials.gov identifier: NCT03676985.

Trial registration: ClinicalTrials.gov identifier: NCT03277924.

Trial registration: ClinicalTrials.gov identifier: NCT03190174.

Trial registration: ClinicalTrials.gov identifier: NCT02304458.

Trial registration: ClinicalTrials.gov identifier: NCT02406781.

Trial registration: ClinicalTrials.gov identifier: NCT02502786.

Trial registration: ClinicalTrials.gov identifier: NCT03860207.

Trial registration: ClinicalTrials.gov identifier: NCT03320330.

Trial registration: ClinicalTrials.gov identifier: NCT03610490.

Trial registration: ClinicalTrials.gov identifier: NCT02100891.

Trial registration: ClinicalTrials.gov identifier: NCT02508038.

Trial registration: ClinicalTrials.gov identifier: NCT03356782.

Trial registration: ClinicalTrials.gov identifier: NCT01953900.

Trial registration: ClinicalTrials.gov identifier: NCT03618381.

Trial registration: ClinicalTrials.gov identifier: NCT03462316.

Trial registration: ClinicalTrials.gov identifier: NCT02487979.     

Nanotechnology approaches for delivery of cytochrome P450 substrates in HIV treatment

ABSTRACT

Introduction: Antiretroviral therapy (ART) has led to a significant reduction in HIV-1 morbidity and mortality. Many antiretroviral drugs (ARVs) are metabolized by cytochrome P450 (CYP) pathway, and the majority of these drugs are also either CYP inhibitors or inducers and few possess both activities. These CYP substrates, when used for HIV treatment in the conventional dosage form, have limitations such as low systemic bioavailability, potential drug–drug interactions, and short half-lives. Thus, an alternative mode of delivery is needed in contrast to conventional ARVs.

Areas covered: In this review, we summarized the limitations of conventional ARVs in HIV treatment, especially for ARVs which are CYP substrates. We also discussed the preclinical and clinical studies using the nanotechnology strategy to overcome the limitations of these CYP substrates. The preclinical studies and clinical studies published from 2000 to February 2019 were discussed.

Expert opinion: Since preclinical and clinical studies for prevention and treatment of HIV using nanotechnology approaches have shown considerable promise in recent years, nanotechnology could become an alternative strategy for daily oral therapy as a future treatment.

Trial registration: ClinicalTrials.gov identifier: NCT02631473.

Trial registration: ClinicalTrials.gov identifier: NCT02165202.

Trial registration: ClinicalTrials.gov identifier: NCT02547870.

Trial registration: ClinicalTrials.gov identifier: NCT02076178.     

Ensifentrine (RPL554): an investigational PDE3/4 inhibitor for the treatment of COPD

ABSTRACT

Introduction: A compound that simultaneously inhibits PDE3 and PDE4 should increase airway caliber by relaxing the smooth muscle and, simultaneously, suppress airway inflammatory responses. Ensifentrine (RPL554) is considered a PDE3/4 inhibitor, although its affinity for PDE3 is 3,440 times higher than that for PDE4, that is under clinical development for the treatment of asthma and COPD and, potentially, cystic fibrosis.

Areas covered: We analyze the development of this molecule from its basic pharmacology to the present clinical Phase II studies.

Expert opinion: Ensifentrine is an interesting drug but there is a lack of solid studies that still does not allow us to correctly allocate this molecule in the current COPD and even asthma therapeutic armamentarium. Furthermore, apparently ensifentrine has not yet entered Phase III clinical development and, in any case, there is no reliable evidence of its ability to elicit an anti-inflammatory activity in patients with COPD or asthma. Therefore, the real anti-inflammatory profile of ensifentrine must be clarified with new studies of basic pharmacology and adequate clinical studies specifically designed. However, at present the most intriguing perspective is linked to its possible use in the treatment of cystic fibrosis, also considering the lack of valid therapeutic options for this disease.

Trial registration: ClinicalTrials.gov identifier: NCT03937479.     

A randomized effectiveness trial of an adult-to-youth mentoring program in Sweden

This report describes an independent evaluation of a psychosocial, adult-to-youth mentoring program run by the Swedish branch of the Mentor Foundation, aiming to prevent substance use in low-risk youth (ClinicalTrials.gov ID: NCT01138982). Eligible 14-year-olds (n?=?128) were randomly assigned to the mentoring program or to a control condition. Baseline and 12-month follow-up measurements included self-reports on emotional, behavioral, and substance use measures from youth and their parents, and grade point average. These were retrieved from school registers at the follow-up. With alpha-levels corrected for multiple comparisons, analyses revealed no statistically significant outcome differences between the two groups. However, a relatively low statistical power and a low program dosage preclude any definite conclusions about program effectiveness. Among the 65 youth assigned to the intervention, those who met with their mentor for a full program period (n?=?33, 51%) were significantly more likely than non-completers to report liking, trusting, and getting help from their mentors. The high rates of premature program terminations highlight the difficulties inherent in implementing mentoring programs under real-world conditions, and the need to strive for adherence to empirically and theoretically derived best practices when doing so. Best practices – such as using mentors with a helping professional background, an ongoing training of mentors, and close monitoring of the mentoring relationships – may be crucial for successful program implementation, and consequently also for the chances of mentoring programs to meet their goals of substance use prevention and improved life quality for the targeted youth.

Trial registration: ClinicalTrials.gov identifier: NCT01138982.     

A randomised study comparing the efficacy and safety of rosuvastatin with atorvastatin for achieving lipid goals in clinical practice in Asian patients at high risk of cardiovascular disease (DISCOVERY-Asia study)

ABSTRACT

Background: Most studies investigating the benefits of statins have focused on North American and European populations. This study focuses on evaluating the lipid-lowering effects of rosuvastatin and atorvastatin in Asian patients.

Objectives: The DIrect Statin COmparison of LDL‐C Values: an Evaluation of Rosuvastatin therapY (DISCOVERY)-Asia study is one of nine independently powered studies assessing the efficacy of starting doses of statins in achieving target lipid levels in different countries worldwide. DISCOVERY-Asia was a 12-week, randomised, open-label, parallel-group study conducted in China, Hong Kong, Korea, Malaysia, Taiwan, and Thailand.

Results: A total of 1482 adults with primary hypercholesterolaemia and high cardiovascular risk (>?20%/10 years, type 2 diabetes, or a history of coronary heart disease) were randomised in a 2?:?1 ratio to receive rosuvastatin 10?mg once daily (o.d.) or atorvastatin 10?mg o.d. The percentage of patients achieving the 1998 European Joint Task Force low-density lipoprotein cholesterol (LDL‐C) goal of <?3.0?mmol/L at 12 weeks was significantly higher in the rosuvastatin group (n = 950) compared with the atorvastatin group (n = 471) (79.5 vs. 69.4%, respectively; p < 0.0001). Similar results were observed for 1998 European goals for total cholesterol (TC), and the 2003 European goals for LDL‐C and TC. LDL‐C and TC levels were reduced significantly more with rosuvastatin compared with atorvastatin. Both drugs were well-tolerated and the incidence and type of adverse events were similar in each group.

Conclusions: This 12-week study showed that the starting dose of rosuvastatin 10?mg o.d. was significantly more effective than the starting dose of atorvastatin 10?mg o.d. at enabling patients with primary hypercholesterolaemia to achieve European goals for LDL‐C and TC in a largely Asian population in real-life clinical practice. The safety profile of rosuvastatin 10?mg is similar to that of atorvastatin 10?mg in the Asian population studied here, and is consistent with the known safety profile of rosuvastatin in the white population.

Trial registration: ClinicalTrials.gov identifier: NCT00241488.     

Teriparatide vertebral fracture risk reduction determined by quantitative and qualitative radiographic assessment

ABSTRACT

Objective: Most registration studies for new osteoporosis drugs have used a combination of quantitative morphometry (QM) and visual semiquantitative reading (SQ) to define vertebral fractures. However, in the pivotal teriparatide Fracture Prevention Trial (ClinicalTrials.gov Identifier: NCT00670501), vertebral fractures were previously defined only by the SQ methodology. The objective of this study was to define the effect of teriparatide on the incidence of vertebral fractures defined by QM plus SQ assessment.

Research design and methods: Radiographs from the Fracture Prevention Trial placebo- and teriparatide 20?μg/day groups were re-assessed in blinded fashion, defining incident vertebral fractures for vertebrae meeting all of the following requirements: (a) 20% decrease in height by QM, (b) a corresponding 4?mm decrease in height (c) an increase of at least one grade by visual SQ assessment by a radiologist.

Results: By this methodology, vertebral fracture risk was reduced in the teriparatide versus placebo group by 84% (RR?=?0.16, p?<?0.001). The risk of two or more vertebral fractures was also significantly reduced by 94% (RR?=?0.06, p?<?0.001). The fractures in the teriparatide group were of lesser severity than the fractures in the placebo group. The absolute benefit of teriparatide was greatest in those patients with the highest number and severity of prevalent vertebral fractures.

Conclusions: As assessed by QM plus SQ, teriparatide reduced the incidence of vertebral fractures.

Trial registration: ClinicalTrials.gov identifier: NCT00670501.     

Effectiveness and safety of recombinant human erythropoietin beta in maintaining common haemoglobin targets in routine clinical practice in Europe: the GAIN study

ABSTRACT

Objective: The Gain effectiveness in Anaemia treatment wIth NeoRecormon^* (epoetin beta) study (GAIN) evaluated the effectiveness and safety of recombinant human erythropoietin beta in correcting and/or maintaining common haemoglobin (Hb) targets in routine clinical practice in Europe.

Research design and methods: European 18-month observational, prospective clinical practice study across 217 centres from 13 countries. During a 3-month retrospective period, patients received any erythropoiesis stimulating agent (ESA). For the subsequent 18-month study phase, patients receiving intravenous (IV) epoetin beta or any other ESA were recommended to be switched to subcutaneous (SC) epoetin beta. Presence of anti-erythropoietin antibodies (AEAB) and related outcomes was investigated before and during the study.

Clinical trial registration: ClinicalTrials.gov number: NCT00551603.

Main outcome measures: Correction and maintenance of Hb levels within recommended target range and mean dose requirement to correct and maintain target Hb levels.

Results: A total of 4264 patients on haemodialysis received an ESA for treatment of renal anaemia. During the study period, the number of patients who maintained Hb levels in the recommended target range of 10–12?g/dL increased from 57% to 62%. Administration of SC epoetin beta resulted in a 24% lower mean dose requirement to maintain target Hb levels compared to IV administration (p?<?0.001). Considerable differences were observed between countries in the study. No patients developed pure red cell aplasia associated with AEAB during observation.

Conclusion: This observational study suggests that haemodialysis patients who are receiving any ESA via SC or IV administration for treatment of their renal anaemia can be safely and effectively switched to SC epoetin beta to achieve or maintain the currently recommended Hb targets. SC required a lower dose than IV administration to maintain similar efficacy, thereby potentially lowering the drug costs.

Trial registration: ClinicalTrials.gov identifier: NCT00551603.     

Treatment preference for weekly versus daily DPP-4 inhibitors in patients with type 2 diabetes mellitus: outcomes from the TRINITY trial

Abstract

Objective: To examine patient preference for treatment with the oral once-weekly dipeptidyl peptidase-4 inhibitor (DPP-4i), trelagliptin, and oral once-daily DPP-4i, alogliptin, administered for 8?weeks each in patients with type 2 diabetes mellitus prescribed a daily DPP-4i.

Methods: In this randomized, open-label, two-way crossover study, patients received trelagliptin followed by alogliptin (T-A group) or alogliptin followed by trelagliptin (A-T group), for 8?weeks each (NCT03231709, JapicCTI-173662). Treatment preference was assessed using a standardized questionnaire in the overall population and by baseline characteristics. Other outcomes included patient satisfaction with diabetes treatment (assessed using the Diabetes Treatment Satisfaction Questionnaire [DTSQ]), hemoglobin A1c (HbA1c) levels after 8?weeks of treatment with each agent, and safety.

Results: Sixty patients from two clinical sites were randomized 1:1 to T-A and A-T groups (each n?=?30); baseline characteristics were similar between groups. After 16?weeks of treatment, 51.7% of patients preferred treatment with alogliptin compared with 30.0% selecting trelagliptin (p?=?.014); preference for alogliptin was consistently greater than for trelagliptin in the secondary analyses by baseline characteristics. DTSQ score and HbA1c levels were similar between treatments after 8?weeks of therapy. Both treatments demonstrated favorable safety and tolerability profiles.

Conclusions: Patients expressed a significantly greater treatment preference for once-daily alogliptin than once-weekly trelagliptin, although patient satisfaction and HbA1c levels were similar across treatments. The decision to administer a once-weekly or once-daily DPP-4i is likely to depend on patient preference, patient-physician discussions, and treatment practices of the prescribing physician.

Trial registration: ClinicalTrials.gov identifier: NCT03231709.     

Ascending single dose pharmacokinetics of cytisine in healthy adult smokers

Abstract

1. Cytisine, a partial agonist for the α₄β₂-nAChR, is used as a smoking cessation medication. Cytisine’s current dosing is complex and involves taking 1.5?mg several times a day. The aim of this study was to explore the effect of dose on the pharmacokinetics and safety of cytisine after a single dose in healthy adult smokers.

2. Participants were assigned to one of three groups (n?=?6 in each group) to receive a single oral dose of 1.5, 3 or 4.5?mg of cytisine. Blood samples were collected up to 24?h post dose. Pulse, blood pressure and respiratory rate were measured. Adverse effects were recorded.

3. Cytisine reached peak plasma concentration 1–2?h post dose in all participants irrespective of dose, with no dose-dependent changes in the elimination phase. Mean (SD) cytisine exposure (AUC_0–24h) were 81.9 (15.8), 181.9 (40.8) and 254.5 (48.1) ng.h/mL following 1.5, 3 and 4.5?mg, respectively.

4. Cytisine appears to have predictable pharmacokinetics following a single dose of up to 4.5?mg and may be safe given as a single 4.5?mg dose, which is threefold greater than the recommended dose taken at one time.

Trial registration: ClinicalTrials.gov identifier: NCT02585024.     

Development of small-molecule immune checkpoint inhibitors of PD-1/PD-L1 as a new therapeutic strategy for tumour immunotherapy

Abstract

Cancer immunotherapy has been increasingly utilised to treat advanced malignancies. The signalling network of immune checkpoints has attracted considerable attention. Immune checkpoint inhibitors are revolutionising the treatment options and expectations for patients with cancer. The reported clinical success of targeting the T-cell immune checkpoint receptors PD-1/PD-L1 has demonstrated the importance of immune modulation. Indeed, antibodies binding to PD-1 or PD-L1 have shown remarkable efficacy. However, antibody drugs have many disadvantages, such as their production cost, stability, and immunogenicity and, therefore, small-molecule inhibitors of PD-1 and its ligand PD-L1 are being introduced. Small-molecule inhibitors could offer inherent advantages in terms of pharmacokinetics and druggability, thereby providing additional methods for cancer treatment and achieving better therapeutic effects. In this review, we first discuss how PD-1/PD-L1-targeting inhibitors modulate the relationship between immune cells and tumour cells in tumour immunotherapy. Second, we discuss how the immunomodulatory potential of these inhibitors can be exploited via rational combinations with immunotherapy and targeted therapy. Third, this review is the first to summarise the current clinical and preclinical evidence regarding small-molecule inhibitors of the PD-1/PD-L1 immune checkpoint, considering features and responses related to the tumours and to the host immune system.

Trial registration: ClinicalTrials.gov identifier: NCT02812875.     

Predictors of heartburn resolution and erosive esophagitis in patients with GERD

ABSTRACT

Objectives: The primary objective was to assess gastroesophageal reflux disease (GERD) symptom resolution rates with esomeprazole by erosive esophagitis (EE) status, and the secondary objective was to evaluate potential predictors of the presence of EE and heartburn resolution.

Background: Patients with GERD who have EE have higher reported symptom resolution rates than those with nonerosive reflux disease (NERD) when treated with proton pump inhibitors (PPIs).

Study: This open-label multicenter study included adults with GERD symptoms. Patients were stratified by EE status after endoscopy and received once-daily esomeprazole 40?mg for 4 weeks. Questionnaires determined symptom response rates, and baseline predictors of EE or heartburn resolution were evaluated. Potential predictors, including years with GERD, history of EE, and time to relief with antacids, were examined.

Results: Heartburn resolution rates at 4 weeks were higher for patients with EE than NERD (69% [124/179] vs. 48% [85/177]; p?<?0.0001). Multivariate models had moderate predictive ability for EE (c-index, 0.76) and poor predictive ability (c-index, 0.57) for heartburn resolution. However, faster heartburn relief with antacid use, particularly within 15?min, was predictive of EE and heartburn resolution.

Conclusions: Patients with EE have higher heartburn resolution rates than patients with NERD after treatment, although recall bias may be possible. Fast relief with antacid use is predictive of EE and heartburn resolution with a PPI and suggests that a history of antacid relief may provide corroborative evidence to empiric PPI therapy in determining whether patients with heartburn have acid reflux disease.

Trial registration: ClinicalTrials.gov identifier: NCT00242736.     

Estimating the potential savings with vagus nerve stimulation for treatment-resistant depression: a payer perspective*

ABSTRACT

Objective: To provide a formula estimating potential reductions in healthcare utilization costs with adjunctive vagus nerve stimulation (VNS Therapy^?) in treatment-resistant depression (TRD).

Methods: This payer-perspective formula incorporates costs of treatment as usual for TRD patients from a published analysis of the MarketScan private payer claims database and the 2004 Medicare 5% standard analytic file. Estimated remission and response rates are from the published VNS pilot and pivotal studies. Costs were converted to 2008 US dollars per the US Bureau of Labor Statistics medical care costs, consumer price index. Device and implantation costs were calculated at $28?336.

Results: From the MarketScan and pooled outcomes data (VNS pilot and pivotal studies), potential per patient savings (hospitalization directly and indirectly related to depression) was $2974 at 5 years of device life, $23?539 at 8 years (moderate cost reduction scenario); $12?914 at 5 years, $40?935 at 8 years (optimistic scenario). Corresponding break-even device life was 4.57 and 3.62 years, respectively. From the Medicare file and pooled outcomes, potential per patient savings (inpatient and outpatient directly and indirectly related to depression) was $8358 at 5 years of device life, $32?385 at 8 years (moderate scenario); $19?837 at 5 years, $52?473 at 8 years (optimistic scenario). Corresponding break-even device life was 3.96 and 3.18 years, respectively.

Conclusions: The formula allows an evaluation of expected reductions in healthcare costs as a function of input cost variables, efficacy rates, and benefit scenarios. Cited costs differ relative to care settings, diagnostic principles, and procedural volume. This formula can help assess moderate-to-longer-term economic benefits of VNS for a particular institution. Results suggested that potential reductions in healthcare costs with VNS for TRD may be substantial. Break-even device life for the scenarios presented ranges between 2.3 and 5.7 years.

Trial registration: ClinicalTrials.gov identifier: NCT00533832.     

Effect of a continuous erythropoietin receptor activator (C.E.R.A.) on stable haemoglobin in patients with CKD on dialysis: once monthly administration*

ABSTRACT

Aims: This Phase II study aimed to determine the optimal dose and administration schedule of continuous erythropoietin receptor activator (C.E.R.A.) given subcutaneously (SC) in patients receiving dialysis converting directly from SC epoetin therapy 1–3 times/week. An extension phase examined long-term safety and efficacy.

Methods: Patients were assigned to one of three C.E.R.A. dose groups determined by multiplying the previous weekly dose of epoetin by one of three ratios (0.4/150, 0.8/150, 1.2/150 for groups A, B and C, respectively). Within each group, patients were randomized to once weekly (QW), once every 3 weeks (Q3W) and once monthly (Q4W) schedules. Dose adjustments were not permitted for the first 6 weeks. The core study period was 19 weeks (21 weeks in the Q4W cohorts). Patients could enter a 12?month extension period at the same schedule, aiming to maintain haemoglobin (Hb) at 11–12?g/dL.

Results: 137 patients entered the core period, and 62 continued into the extension period. A dose-dependent relationship was seen in the primary efficacy variable, change in Hb standardized to a 6 week period (?p < 0.0001), but effect was independent of schedule. Hb levels were maintained throughout the study, with few dose changes. C.E.R.A. was generally well tolerated and the most frequent adverse event was hypotension.

Conclusion: The results suggest that SC C.E.R.A. at up to once monthly intervals provides stable maintenance of Hb levels in dialysis patients converting directly from epoetin 1–3 times/week. Achieving tight Hb control with few dose adjustments at extended administration intervals may offer health benefits and improvements in resource management.

Trial registration: ClinicalTrials.gov identifier: NCT00364832.     

Anemia treatment with Q2W darbepoetin alfa in patients with chronic kidney disease naïve to erythropoiesis-stimulating agents*

ABSTRACT

Objective: To evaluate the efficacy and safety of darbepoetin alfa dosed every-other-week (Q2W) to treat anemia in subjects with chronic kidney disease (CKD), not receiving dialysis, who were naïve to erythropoiesis-stimulating agent (ESA) therapy.

Research design and methods: This was an open-label, multicenter, single-arm study enrolling ESA-naïve CKD subjects with baseline hemoglobin (Hb)?<?11.0?g/dL. Q2W darbepoetin alfa treatment was initiated at a dose of 0.75?µg/kg and titrated to achieve and maintain Hb levels at 11.0–13.0?g/dL. Treatment was administered from week 1 to week 19.

Main outcome measures: The primary endpoint was the proportion of subjects who achieved Hb?≥?11?g/dL at any study visit, except in week 1. Hb levels, darbepoetin alfa dose, and safety were also assessed.

Results: Of the 128 subjects who received at least one dose of darbepoetin alfa and of the subjects who completed the study, 118 (92%) and 112 (97%), respectively, achieved a Hb?≥?11?g/dL in a median time of 5 weeks. Median darbepoetin alfa dose at week 1 and at the time of achieving a Hb?≥?11?g/dL were 60 and 80?µg, respectively. Darbepoetin alfa was well-tolerated, and short-term adverse events were consistent with those expected in CKD subjects.

Conclusions: This study demonstrates that de novo Q2W darbepoetin alfa was effective in correcting and maintaining Hb levels in ESA-naïve subjects with CKD who were not receiving dialysis. Study limitations, including lack of a control arm for the study and multiple race information for subjects, must be considered in interpreting the results.

Trial registration: ClinicalTrials.gov identifier: NCT00112008.     

Efficacy and safety of sitagliptin added to ongoing metformin therapy in patients with type 2 diabetes

ABSTRACT

Objective: The purpose of this study was to evaluate the efficacy and safety of sitagliptin as an add-on to metformin therapy in patients with moderately severe (hemoglobin A_1c ≥?8.0% and ≤?11.0%) type 2 diabetes mellitus (T2DM).

Research design and methods: This was a multi­national, randomized, placebo-controlled, parallel-group, double-blind study conducted in 190 patients with T2DM. After ≥?6?weeks of stable metformin monotherapy (≥?1500?mg/day), patients were randomized to either the addition of sitagliptin 100?mg once daily or placebo to ongoing metformin for 30?weeks.

Main outcome measures: The primary efficacy endpoint was reduction in hemoglobin A_1c (HbA_1c) measured after 18?weeks of sitagliptin treatment. Key secondary end­points included reduction in fasting plasma glucose (FPG) and 2-hour (2-h) postprandial plasma glucose (PPG) at 18 weeks, and HbA_1c at 30 weeks. The proportion of patients meeting the goal of HbA_1c <?7.0% was also analyzed.

Results: Sitagliptin significantly reduced HbA_1c, FPG, and 2-h PPG, compared with placebo (all p < 0.001). The net improvement in HbA_1c was –1.0% at both 18 and 30 weeks, and a significantly greater proportion of patients treated with sitagliptin achieved HbA_1c <?7.0% by the end of the study (22.1% vs. 3.3%, p < 0.001). Sitagliptin was well-tolerated. Compared with placebo, sitagliptin had a neutral effect on body weight and did not signif­icantly increase the risk of hypoglycemia or gastro­intestinal adverse events.

Conclusions: Addition of sitagliptin 100?mg once daily to ongoing metformin therapy was well-tolerated and resulted in significant glycemic improvement in patients with moderately severe T2DM who were treated for 30 weeks.

Trial registration: ClinicalTrials.gov identifier: NCT00337610.     

Verteporfin PDT for subfoveal occult CNV in AMD: two-year results of a randomized trial

ABSTRACT

Objective: To determine whether verteporfin photodynamic therapy (PDT) can safely reduce the risk of vision loss in patients with subfoveal occult with no classic choroidal neovascularization (CNV) due to age-related macular degeneration.

Research design and methods: Eligible patients were ≥50 years of age with lesion size ≤6 disc areas and best-corrected vision 20/40–20/200. A total of 364 patients with occult with no classic CNV were randomly assigned 2 : 1 to verteporfin PDT (n?=?244) or placebo (n?=?120). The primary outcome measures were loss of ≥15 and ≥30 letters of visual acuity (VA) from baseline at 12 and 24 months.

Results: A total of 37% and 47% of verteporfin-treated patients versus 45% and 53% of placebo recipients lost ≥15 letters of VA at month 12 and month 24, respectively; 16% and 23% of verteporfin-treated patients versus 17% and 25% of placebo recipients lost ≥30 letters at month 12 and month 24, respectively. These differences were not statistically significant. Four (1.6%) verteporfin-treated patients and one placebo patient (who received verteporfin in error) experienced an acute severe VA decrease; all five patients recovered some degree of vision. No unexpected ocular or systemic adverse events were identified.

Conclusions: Verteporfin PDT in the treatment of occult with no classic CNV was safe and well-tolerated. The differences between the two groups in the primary efficacy variables were not significant. Baseline characteristics and patient selection methods may have contributed to the small treatment effect.

Trial registration: ClinicalTrials.gov identifier: NCT00121407.     

Effects of tolterodine ER on patient-reported outcomes in sexually active women with overactive bladder and urgency urinary incontinence

ABSTRACT

Objective: To assess the effects of tolterodine extended release (ER) on patient-reported outcomes (PROs) in sexually active women with overactive bladder (OAB) and urgency urinary incontinence (UUI).

Research design and methods: This multicenter, double-blind, placebo controlled trial included 411 women aged?≥18 years reporting OAB symptoms for ≥3 months; ≥8 micturitions per 24 hours (including ≥0.6 UUI episodes and ≥3 OAB micturitions) in 5-day bladder diaries at baseline, and being in a sexually active relationship for ≥6 months. Subjects randomized to placebo or tolterodine ER completed validated OAB- or incontinence-specific questionnaires, including the Patient Perception of Bladder Condition (PPBC), Overactive Bladder Questionnaire (OAB-q), Urgency Perception Scale (UPS), and the Incontinence Impact Questionnaire (IIQ) at baseline and week 12, as well as the Perception of Treatment Benefit and Treatment Satisfaction questions at week 12. This study is registered with ClinicalTrials.gov (identifier: NCT00143481)

Results: The mean age of enrolled women was approximately 48 years. Compared with placebo, the tolterodine ER group reported significant baseline to week 12 improvements in PPBC responses (p?=?0.0048); OAB-q Symptom Bother, total Health-Related Quality of Life (HRQL), and HRQL domain scores (all p?<?0.05); IIQ Emotional Health domain scores (p?<?0.05); proportions of subjects reporting treatment benefit (79 vs. 54%; p?<?0.0001) and satisfaction (78 vs. 59%; p?<?0.0001). Improvements on the UPS were not significantly different.

Conclusions: Tolterodine ER treatment was associated with improvements in multiple OAB- and incontinence-specific PROs in a sexually active, relatively young, and racially diverse population of women. The findings provide clinicians with new insights into the impact of OAB and its treatment on HRQL in this population, which has been underrepresented in previous OAB studies. Study limitations include a potential underestimation of the impact of OAB symptoms resulting from the exclusion of women who may not be sexually active because of their urinary symptoms.

Trial registration: ClinicalTrials.gov identifier: NCT00143481.     

A randomised controlled trial of a new 2 litre polyethylene glycol solution versus sodium picosulphate + magnesium citrate solution for bowel cleansing prior to colonoscopy*

ABSTRACT

Background: A new 2?L polyethylene glycol (PEG) solution containing ascorbic acid (Asc) and electrolytes (Moviprep^?) has been developed for bowel cleansing.

Objectives: To compare the efficacy, safety and acceptability of PEG + Asc versus sodium picosulphate + magnesium citrate in patients scheduled to undergo colonoscopy.

Design and methods: This single blind, parallel group pilot study included 65 adult male and female patients. A blinded assessment of cleansing was made for each bowel segment by the colonoscopist and the scores determined an overall grading of bowel cleansing. Patients completed a questionnaire on the acceptability of the preparation.

Results: Successful bowel preparation was reported in 84.4% of patients who received PEG + Asc and 72.7% of patients who received sodium picosulphate + magnesium citrate (treatment difference +11.6, 95% CI –11.2, +34.5; p = 0.367). Patients were more likely to have a higher overall quality of bowel cleansing with PEG + Asc (?p = 0.018), with specifically better cleansing in the ascending colon (?p = 0.024) and caecum (?p = 0.003) compared with patients who received sodium picosulphate + magnesium citrate. The adverse event profile of the two treatments was similar, with headache and gastrointestinal effects being the most commonly reported. Some patient acceptability results favoured sodium picosulphate + magnesium citrate for those patients who had experience of previous bowel preparation, but were similar for those patients who had not had a previous bowel preparation.

Conclusions: PEG + Asc provided effective bowel cleansing, which was equivalent to that of sodium picosulphate + magnesium citrate in terms of grading cleansing as overall success or failure. In the proximal colon (ascending colon and caecum) PEG + Asc provided significantly better cleansing to that achieved with sodium picosulphate + magnesium citrate.

Trial registration: ClinicalTrials.gov identifier: NCT00312481.     

Levofloxacin versus azithromycin on the oropharyngeal carriage and selection of antibacterial- resistant streptococci in the microflora of healthy adults

ABSTRACT

Objective: To determine the proportion of subjects with oropharyngeal streptococci resistant to either levofloxacin or azithromycin prior to and during antibacterial exposure, and to follow temporal changes in the proportion of resistant and susceptible isolates through 6 weeks post-exposure. This randomized, open-label, single-center study is registered with ClinicalTrials.gov (identifier: NCT00821?782).

Research design and methods: A total of 143 healthy volunteers (levofloxacin, n?=?71; azithromycin, n?=?72) without antibacterial exposure in the previous 90 days received either levofloxacin 750?mg once daily for 5 days or azithromycin 500?mg once daily on day 1 and 250?mg once daily on days 2 through 5. Oropharyngeal cultures were obtained pre-exposure, at day 5, and at 2, 4, and 6 weeks post-dosing. Bacterial strains were identified and the minimum inhibitory concentrations for levofloxacin and azithromycin were determined.

Results: At study entry 117 streptococci were isolated from 72 subjects randomized to azithromycin and 53 (45.3%) were azithromycin-resistant. None of the 121 streptococci isolated from 71 subjects randomized to.levofloxacin were colonized by a levofloxacin-resistant microorganism prior to dosing. At the end of dosing, the number of subjects with resistant streptococci (S. mitis, S. salivarius, S. sanguis, or alpha streptococcus species [spp.]) increased in azithromycin-exposed subjects and resistant isolates remained through 6 weeks post-dosing. In contrast, a small number of levofloxacin-resistant streptococci were observed at the end of dosing but decreased by week 2 post-dosing and continued to decrease through the 6-week evaluation period (p?<?0.001 azithromycin vs. levofloxacin for S. mitis, S. salivarius, S. sanguis and alpha streptococcus spp. at week 6). Limitations of this study included the fact that, since previous antibiotic use was self-reported, genetic typing was not done. The results of this study may not be completely generalizable, because subjects in this study received study drug under directly-observed conditions, thus ensuring compliance.

Conclusions: Both antibacterial agents were well tolerated. Levofloxacin 750?mg administered for 5 days was associated with less microbial resistance than that observed with azithromycin in healthy subjects.

Trial registration: ClinicalTrials.gov identifier: NCT00821782.