Designs of RADIANCE 1 and 2:carotid ultrasound studies comparing the effects of torcetrapib/atorvastatin with atorvastatin alone on atherosclerosis*

ABSTRACT

Objective: The RADIANCE studies were designed to assess the effects of torcetrapib/atorvastatin (T/A) compared with atorvastatin alone on slowing atherosclerotic progression in patients with heterozygous familial hypercholesterolemia (RADIANCE 1) or mixed hyperlipidemia (RADIANCE 2), as measured by change in carotid intima-media thickness (CIMT).

Research design and methods: RADIANCE 1 and 2 were random­ized, double-blind, controlled trials with a duration of 2 years. In both studies, eligible subjects began treatment with atorvastatin during a run-in period and were titrated to target LDL?C levels defined by NCEP ATP III guidelines. Subjects then proceeded to a double-blind randomized treatment period where they received one of two regimens: (i) fixed combination T/A (torcetrapib dose, 60?mg), or (ii) atorvastatin alone. In both regimens, the dose of atorvastatin was established during the run-in period (20–80?mg, RADIANCE 1; 10–80?mg RADIANCE 2). B-mode ultrasonography was performed in duplicate at baseline and at end of study, and every 6 months in between.

Main outcome measures: The primary efficacy measure in both studies was the annualized rate of change in maximum CIMT of 12 pre-defined carotid segments. Further outcome measures included lipid and safety assessments.

Current status: The number of subjects randomized was 904 in RADIANCE 1 and 752 in RADIANCE 2. Results are anticipated in 2007.

Trial registration: ClinicalTrials.gov identifier: NCT00136981.

Trial registration: ClinicalTrials.gov identifier: NCT00134238.     

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.     

The economic burden of fibromyalgia: comparative analysis with rheumatoid arthritis*

ABSTRACT

Objective: To quantify and compare direct costs, utilization, and the rate of comorbidities in a sample of patients with fibromyalgia (FM), a poorly understood illness associated with chronic widespread pain that is commonly treated by rheumatologists, to patients with rheumatoid arthritis (RA), a well studied rheumatologic illness associated with inflammatory joint pain. Patients with both illnesses were isolated and reported as a third group. A secondary analysis of work loss was performed for an employed subset of these patients.

Research design and methods: Retrospective cohort analysis of Thomson Reuters MarketScan administrative healthcare claims and employer-collected absence and disability data for adult patients with a diagnosis of FM (ICD-9-CM 729.1) and/or RA (ICD-9-CM 714.0x,–714.3x) on at least one inpatient or two outpatient claims during 2001–2004.

Main outcome measures: The 12-month healthcare utilization, expenditures, and rates of comorbidities were quantified for all study-eligible patients; absence and short-term disability days and costs were quantified for an employed subset.

Results: The sample included 14?034 FM, 7965 RA, and 331 FM?+?RA patients. Patients with FM had a higher prevalence of several comorbidities and greater emergency department (ED) utilization than those with RA. Mean annual expenditures for FM patients were $10?911 (SD?=?$16?075). RA patient annual expenditures were similar to FM: $10?716 (SD?= $16?860). Annual expenditures were almost double in patients with FM+RA ($19?395, SD?= $25?440). A greater proportion of patients with FM had any short-term disability days than those with RA (20 vs. 15%); and a greater proportion of patients with RA had any absence days (65 vs. 80%). Mean costs for absence from work and short-term disability in the FM and RA groups were substantial and similar. The FM+RA group was of insufficient sample size to report on work loss.

Limitations: The availability of newer and more expensive FDA-approved medications since 2004 is not reflected in our findings. This analysis was restricted to commercially insured patients and therefore may not be generalizable to the entire U.S. population.

Conclusions: The burden of illness in FM is substantial and comparable to RA. Patients with FM incurred direct costs approximately equal to RA patients. Patients with FM had more ED, physician, and physical therapy visits than RA patients. Patients in both groups had several comorbidities. Patients with FM+RA incurred direct costs almost double those of the patients with either diagnosis alone. FM and RA patients incurred similar overall absence and short-term disability costs.     

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.     

Carotid intima-media thickness in low-risk individuals with asymptomatic atherosclerosis: baseline data from the METEOR study*

ABSTRACT

Objective: Carotid intima-media thickness (CIMT) is an index for changes in atherosclerosis burden and changes in CIMT may relate to clinical events. We present baseline data from the METEOR study, a randomized, placebo-controlled trial evaluating the efficacy of rosuvastatin 40?mg on changes in CIMT. We set out to compare differ­ences in CIMT between several subgroups of individuals.

Design and methods: A total of 984 individuals aged 45–70 years (men) or 55–70 (women) were randomized. Participants were required to have: maximum CIMT ≥?1.2–<?3.5?mm; 2+ risk factors and 10-year coronary heart disease (CHD) risk <?10%, or <?2 CHD risk factors. Demo­graphic characteristics were compared in two groups: USA versus Europe, and individuals with maximum CIMT <?2?mm versus those with CIMT ≥?2?mm.

Baseline data: Overall, mean age was 57 years and mean low-density lipoprotein cholesterol was 152?mg/dL (3.9?mmol/L). Body mass index (BMI), triglyceride and high-sensitivity C-reactive protein levels were all higher in US individuals, whereas smoking, hypertension and high-density lipoprotein cholesterol levels were higher in Europeans. Mean CIMT levels were the same in both populations, and the percentage of individuals with ≥?2 CHD risk factors was similar. Increased baseline CIMT (>?2?mm) was related to increasing age, male gender, smoking, hypertension and lipid levels.

Conclusions: In this global trial, differences in baseline characteristics between participants from the USA and Europe are apparent. However, a strong association between CIMT and several cardiovascular risk factors was observed across the two continents.

Trial registration: ClinicalTrials.gov identifier: NCT00225589.     

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.     

Effectiveness of fluticasone furoate 110 μg once daily in the treatment of nasal and ocular symptoms of seasonal allergic rhinitis in adults and adolescents sensitized to mountain cedar pollen*

ABSTRACT

Background: Fluticasone furoate (FF) is a novel enhanced-affinity corticosteroid for the treatment of allergic rhinitis, delivered by a unique side-actuated device. This study was designed to investigate the efficacy and safety of FF nasal spray (FFNS) 110?μg once daily compared with placebo in adults and adolescents (aged ≥12?years) with seasonal allergic rhinitis (SAR) symptoms caused by mountain cedar (Juniperus ashei) pollen.

Methods: This was a randomized, double-blind, placebo-controlled, parallel-group, phase?III study conducted over a 2-week period (between 10 December 2004 and 19 January 2005) at seven study sites, in Austin, Texas, USA, and San Antonio, Texas, two metropolitan cities in the central Texas Hill Country located approximately 80 miles apart. Adult and adolescent patients (aged ≥12?years) with SAR, who were sensitized to mountain cedar (Juniperus ashei) pollen, were randomized to receive either FFNS 110?μg (n?=?152) or placebo (n?=?150) once daily. Patients rated the severity of each nasal symptom (rhinorrhea, nasal congestion, nasal itching, and sneezing) and ocular symptom (redness, watery eyes, itching and burning) on a 4-point categorical scale (0?=?none, 3?=?severe) in a reflective and instantaneous manner. Patients also rated their overall evaluation of response to therapy.

Results: FFNS significantly improved the nasal symptoms of SAR compared with placebo. The least square (LS) mean difference in the reflective total nasal symptom score (TNSS) was ?0.777 (p?=?0.003). A significant reduction in morning pre-dose instantaneous TNSS was also observed compared with placebo (LS mean difference ?0.902; p?<?0.001). Patients receiving FFNS had significantly greater improvements from baseline in reflective total ocular symptom scores (TOSS) than those receiving placebo (LS mean difference ?0.546; p?=?0.008). Significant improvements in ocular symptoms with FFNS versus placebo were also observed for morning pre-dose instantaneous TOSS (LS mean difference ?0.519; p?=?0.009). FFNS had a favorable safety and tolerability profile: fewer adverse events occurred with FFNS (22%) than with placebo (29%), and no serious adverse events were observed.

Conclusions: FFNS?110?μg once daily demonstrated efficacy in relieving both the nasal and ocular symptoms of SAR in adult and adolescent patients.

Trial registration: ClinicalTrials.gov identifier: NCT00115622.     

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.     

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.     

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.     

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.     

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.     

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.     

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.     

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.     

Healthcare resource utilization and costs among women diagnosed with uterine fibroids compared to women without uterine fibroids

Objective: To perform a retrospective, matched-cohort, longitudinal evaluation of annual pre- and post-diagnosis costs incurred among women with uterine fibroids (UF) (cases) compared to controls without UF.

Methods: Data were derived from the IBM Watson Health MarketScan Commercial Claims and Encounters and Medicaid Multi-State databases. Women aged 18–64?years with ≥1 inpatient or outpatient medical claim with an initial UF diagnosis (index date) from 1 January 2010 to 31 December 2014 were included. Healthcare resource utilization (HCRU) data including pharmacy, outpatient and inpatient hospital claims were collected for 1?year pre-index and ≤5?years post-index. All-cause costs (adjusted to 2017 $US) were compared between cases and controls using multivariable regression models.

Results: Analysis included 205,098 (Commercial) and 24,755 (Medicaid) case–control pairs. HCRU and total all-cause healthcare costs were higher for cases versus controls during the pre-index year and all years post-index. Total unadjusted mean all-cause costs were $1197 higher (p?<?.0001; Commercial) and $2813 higher (standardized difference 0.08; Medicaid) for cases during the pre-index year. Total adjusted mean all-cause costs in the first year post-index were $14,917 for cases versus $5717 for controls in the Commercial population, and $20,244 versus $10,544, respectively, in the Medicaid population. In Years 2–5 post-index, incremental mean adjusted total costs decreased, but remained significantly higher for cases versus controls at all time points in both populations (all p?<?.05).

Conclusions: Costs were higher for women with UF compared to women without UF during the pre-index year and over 5?years post-index; differences were greatest in the first year post-index.     

Randomized,double-blind,placebo-controlled trial of every-3-week darbepoetin alfa 300 micrograms for treatment of chemotherapy-induced anemia

ABSTRACT

Objective: Darbepoetin alfa is effective in treating chemotherapy-induced anemia (CIA). Administration of subcutaneous darbepoetin alfa every 3 weeks (Q3W) could simplify treatment through synchronization with common Q3W chemotherapy regimens. We report results from a multicenter, randomized, double-blind, placebo-controlled, phase 3 trial evaluating the efficacy and safety of fixed-dose Q3W darbepoetin alfa in patients with a wide variety of tumor types who experienced CIA.

Research design and methods: Patients aged?≥?18 years with anemia (hemoglobin <11?g/dL) being treated for nonmyeloid malignancy were randomized 1:1 to receive darbepoetin alfa 300?μg (n?=?193) or placebo (n?=?193) subcutaneously Q3W from weeks 1 to 13 in this 16-week study. Doses could be adjusted per prespecified rules.

Main outcome measures: The primary endpoint was the proportion of patients who received ≥1 red blood cell (RBC) transfusion between week 5 and the end of the treatment period (EOTP). The study also analyzed the proportions of patients achieving a hemoglobin concentration ≥11?g/dL and subsequently maintaining hemoglobin levels above 11?g/dL, and the change in hemoglobin concentration over time.

Results: The proportion of patients requiring RBC transfusions between week 5 and EOTP was significantly lower in the darbepoetin alfa-treated group than in the placebo-treated group (24 vs. 41% of patients, a 16.3% difference, p?<?0.001). There were no differences between the two treatment arms in quality-of-life measures. Cardiovascular/thromboembolic adverse events were uncommon and were not associated with increases in hemoglobin levels. Study limitations suggest caution in the interpretation of these results: transfusions, the primary endpoint, were recommended but not required if hemoglobin concentrations were ≤8.0?g/dL, and protocol deviations (primarily dosing errors) occurred in approximately one-half of the patients in both treatment groups.

Conclusions: In this study, fixed-dose Q3W darbepoetin alfa appeared to be well-tolerated and effective for the treatment of CIA.

Trial registration: ClinicalTrials.gov identifier: NCT00110955.     

Duloxetine versus escitalopram and placebo in the treatment of patients with major depressive disorder: onset of antidepressant action,a non-inferiority study*

ABSTRACT

Objective: The goal of a non-inferiority study is to test whether a new treatment has at least as much efficacy as an established treatment¹. The purpose of this non-inferiority study was to compare the speed of onset of antidepressant efficacy for duloxetine (a dual serotonin and norepinephrine reuptake inhibitor) and escitalopram (a selective serotonin reuptake inhibitor).

Research design and methods: This was a randomized, double-blind, placebo- and active comparator-controlled study, in which patients (≥ 18 years) meeting DSM?IV criteria for Major Depressive Disorder (MDD) received duloxetine 60?mg once daily (QD; N = 273), escitalopram 10?mg QD (N = 274), or placebo (N = 137) for 8 weeks. The primary objective was to compare the onset of antidepressant efficacy, by testing the hypothesis that the percentage of duloxetine-treated patients achieving onset criteria at Week 2 was not inferior to that in the escitalopram group.

Main outcome measures: Onset of efficacy was defined as a 20% decrease from baseline on the 17?item Hamilton Rating Scale for Depression (HAMD₁₇) Maier subscale that was maintained or exceeded at all subsequent visits.

Results: Probabilities of meeting onset criteria at Week 2 for duloxetine- and escitalopram-treated patients were 42.6% versus 35.2%, respectively (treatment difference = 7.4%; 95% confidence interval, –1.3% to 16.2%; p = 0.097). Both drugs showed significant improvement compared with placebo (?p ≤ 0.05) on the primary efficacy measure (Maier subscale) at Week 1 and endpoint (Week 8). No differences were found between duloxetine, escitalopram, and placebo rates of remission or response at 8 weeks. Adverse events that occurred significantly more frequently among duloxetine-treated patients when compared with those receiving escitalopram were nausea, dry mouth, vomiting, yawning, and irritability. The rate of discontinuation due to adverse events did not differ significantly between treatment groups.

Limitations: Given the difficulties in constructing appropriate dose comparisons, the results of this study should be interpreted specific to the doses tested and not extrapolated to the drug as a whole. This study employed a fixed-dose design; flexible-dose designs are more likely to find a difference between antidepressants and placebo.

Conclusion: In this study, both duloxetine and escitalopram showed significantly greater improvement on the primary efficacy measure than placebo over the 8?week acute treatment period, while no differences were observed between drugs or between drugs and placebo on response and remission rates at 8 weeks. Escitalopram at a starting dose of 10?mg QD was better tolerated than duloxetine at a starting dose of 60?mg QD. This study met its pre-defined primary objective of assessing if duloxetine was non-inferior to escitalopram in antidepressant onset efficacy, and the results show that duloxetine is at least as fast as (non-inferior to) escitalopram.

Trial registration: ClinicalTrials.gov identifier: NCT00073411.