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Background/Aims: Combinations of treatments that have already received regulatory approval can offer additional benefit over Each of the treatments individually. However, trials of these combinations are lower priority than those that develop novel therapies, which can restrict funding, timelines and patient availability. This article develops a novel trial design to facilitate the evaluation of New combination therapies. This trial design combines elements of phase II and phase III trials to reduce the burden of evaluating combination therapies, while also maintaining a feasible sample size. This design was developed for a randomised trial that compares the properties of three combination doses of ketamine and dexmedetomidine, given intranasally, to ketamine delivered intravenously for children undergoing a closed reduction for a fracture or dislocation. Methods: This trial design uses response-adaptive randomisation to evaluate different dose combinations and increase the information collected for successful novel drug combinations. The design then uses Bayesian dose-response modelling to undertake a comparative effectiveness analysis for the most successful dose combination against a relevant comparator. We used simulation methods determine the thresholds for adapting the trial and making conclusions. We also used simulations to evaluate the probability of selecting the dose combination with the highest true effectiveness the operating characteristics of the design and its Bayesian predictive power. Results: With 410 participants, five interim updates of the randomisation ratio and a probability of effectiveness of 0.93, 0.88 and 0.83 for the three dose combinations, we have an 83% chance of randomising the largest number of patients to the drug with the highest probability of effectiveness. Based on this adaptive randomisation procedure, the comparative effectiveness analysis has a type I error of less than 5% and a 93% chance of correcting concluding non-inferiority, when the probability of effectiveness for the optimal combination therapy is 0.9. In this case, the trial has a greater than 77% chance of meeting its dual aims of dose-finding and comparative effectiveness. Finally, the Bayesian predictive power of the trial is over 90%. Conclusions: By simultaneously determining the optimal dose and collecting data on the relative effectiveness of an intervention, we can minimise administrative burden and recruitment time for a trial. This will minimise the time required to get effective, safe combination therapies to patients quickly. The proposed trial has high potential to meet the dual study objectives within a feasible overall sample size. [ABSTRACT FROM AUTHOR]

Androgen‐deprivation therapy (ADT) is an effective treatment for men with advanced prostate cancer, but loss of bone mineral density (BMD) is a major risk factor for fractures. This review compared the efficacy of available treatments to provide prescribing guidance to healthcare professionals. This is the first review to compare the effectiveness of different osteoporotic treatments (bisphosphonates, denosumab, toremifene, and raloxifene) on BMD in patients with non‐metastatic prostate cancer on ADT using network meta‐analysis. Results suggest that all evaluated treatments are effective in improving BMD compared to placebo. Zoledronic acid (ZA) was found to have a greater improvement in BMD compared to other active treatments at all three studied sites, except for risedronate, which had better BMD improvement compared to ZA at the femoral neck site in one small study. Our study did not identify evidence that one drug is unequivocally more effective than another. All drugs appeared to be effective in reducing the rate of bone loss. Healthcare professionals should also consider patient preference, costs, and local availability as part of the decision process. [ABSTRACT FROM AUTHOR]

Purpose To use patient-level microsimulation models to evaluate the comparative cost-effectiveness of early corneal cross-linking (CXL) and conventional management with penetrating keratoplasty (PKP) when indicated in managing keratoconus in Canada. Design Cost-utility analysis using individual-based, state–transition microsimulation models. Participants Simulated cohorts of 100 000 individuals with keratoconus who entered each treatment arm at 25 years of age. Fellow eyes were modeled separately. Simulated individuals lived up to a maximum of 110 years. Methods We developed 2 state–transition microsimulation models to reflect the natural history of keratoconus progression and the impact of conventional management with PKP versus CXL. We collected data from the published literature to inform model parameters. We used realistic parameters that maximized the potential costs and complications of CXL, while minimizing those associated with PKP. In each treatment arm, we allowed simulated individuals to move through health states in monthly cycles from diagnosis until death. Main Outcome Measures For each treatment strategy, we calculated the total cost and number of quality-adjusted life years (QALYs) gained. Costs were measured in Canadian dollars. Costs and QALYs were discounted at 5%, converting future costs and QALYs into present values. We used an incremental cost-effectiveness ratio (ICER = difference in lifetime costs/difference in lifetime health outcomes) to compare the cost-effectiveness of CXL versus conventional management with PKP. Results Lifetime costs and QALYs for CXL were estimated to be Can$5530 (Can$4512, discounted) and 50.12 QALYs (16.42 QALYs, discounted). Lifetime costs and QALYs for conventional management with PKP were Can$2675 (Can$1508, discounted) and 48.93 QALYs (16.09 QALYs, discounted). The discounted ICER comparing CXL to conventional management was Can$9090/QALY gained. Sensitivity analyses revealed that in general, parameter variations did not influence the cost-effectiveness of CXL. Conclusions CXL is cost-effective compared with conventional management with PKP in the treatment of keratoconus. Our ICER of Can$9090/QALY falls well below the range of Can$20 000 to Can$100 000/QALY and below US$50 000/QALY, thresholds generally used to evaluate the cost-effectiveness of health interventions in Canada and the United States. This study provides strong economic evidence for the cost-effectiveness of early CXL in keratoconus. [ABSTRACT FROM AUTHOR]

Background: New targeted therapeutics for metastatic renal cell carcinoma (mRCC) enable an increment in progression-free survival (PFS) ranging from 2 to 6 months. Compared with best supportive care, everolimus demonstrated an additional PFS of 3 months in patients with mRCC whose disease had progressed on sunitinib and/or sorafenib. The only targeted therapy for mRCC currently reimbursed in Serbia is sunitinib. Objective: The aim of this study was to estimate the cost-effectiveness and the budget impact of the introduction of everolimus in Serbia in comparison to best supportive care, for mRCC patients refractory to sunitinib. Methods: A Markov model was designed corresponding with Serbian treatment protocols. A health care payer perspective was taken, including direct costs only. Treated and untreated cohorts were followed up over 18 cycles, each cycle lasting 8 weeks, which covered the lifetime horizon of mRCC patients refractory to the first-line treatment. Annual discounted rates of 1.5% for effectiveness and 3% for costs were applied. Transitions between health states were modeled by time-dependent probabilities extracted from published Kaplan-Meier curves of PFS and overall survival (OS). Utility values were obtained from the appraisals of other mRCC treatments. One-way and probabilistic sensitivity analyses were done to test the robustness and uncertainty of the base-case estimate. Lastly, the potential impacts of everolimus on the overall health care expenditures on annual and 4-year bases were estimated in the budget-impact analysis. Results: The incremental cost-effectiveness ratio for everolimus was estimated at €86,978 per quality-adjusted life-year. Sensitivity analysis identified the hazard multiplier, a statistical approximator of OS gain, as the main driver of everolimus cost-effectiveness. Furthermore, probabilistic sensitivity analyses revealed a wide 95% CI around the base-case incremental cost-effectiveness ratio estimate (€32,594–€425,258 per quality-adjusted life-year). Finally, an average annual budgetary impact of everolimus in first 4 years after its potential reimbursement would be around €270,000, contributing to <1% of the total budget in Serbian oncology. Conclusions: Everolimus as a second-line treatment of mRCC is not likely to be a cost-effective option under the present conditions in Serbia, with a relatively limited impact on its budget in oncology. A major constraint on the estimation of the cost- effectiveness of everolimus relates to the uncertainty around the everolimus effect on extending OS. How- ever, prior to a final decision on the acceptance/ rejection of everolimus, reassessment of the whole therapeutic group might be needed to construct an economically rational treatment strategy within the mRCC field. [ABSTRACT FROM AUTHOR]

Background: Albuminuria is a marker for renal and cardiovascular (CV) risk, allowing early diagnosis of subjects with elevated renal and CV risk. Objective: This study aimed to estimate the costeffectiveness and budget impact of various population-based screen-and-treat scenarios for elevated albuminuria levels (ie, microalbuminuria) in the Netherlands. Methods: A multistate transition Markov model was developed to simulate the natural course of albuminuria-based disease progression to dialysis and occurrence of CV events. Several population-based strategies directed at screening for elevated albuminuria were evaluated. These strategies depended on urinary albumin concentration (UAC), urinary albumin excretion (UAE), and age. Transition probabilities were derived from the observational community-based Prevention of Renal and Vascular End Stage Disease (PREVEND) cohort study. Health care costs (in year-2008 euros) and life-years gained were calculated over an 8-year period. In the base-case analysis, we analyzed screening for and treatment of microalbuminuria. Screening for microal-buminuria involved prescreening for UAC ≥20 mg/L, followed by a confirmation test for UAE ≥30 mg/d. Other options based on combinations of albuminuria for UAC prescreening (no prescreening, and ≥10, ≥20, ≥100, and ≥200 mg/L) and UAE confirmation test (≥15, ≥30, and ≥300 mg/d) for treatment were investigated in scenario analyses. Furthermore, these various strategies based on UAC and UAE values were analyzed in different subgroups based on age (all ages, aged ≥50 years, and aged ≥60 years). Results: The PREVEND study included 8592 Dutch residents aged 28 to 75 years at the time of initial screening. Among a hypothetical cohort of 1000 subjects identified and treated in the base-case analysis, it was estimated (based on PREVEND follow-up data) that, in the screening/treatment and no-screening scenarios, 76 versus 124 CV events occurred, 16 versus 27 CV deaths, and 3 versus 5 dialysis cases, respectively. The per-person difference in net costs for screening was calculated at €926 (€2003 vs €1077), and prevention of CV deaths was estimated to gain 0.0421 discounted life-year per person. Correspondingly, the cost-effectiveness was estimated at €22,000 per life-year gained. In the base-case analysis, probabilistic sensitivity analysis indicated that the likelihood of cost-effectiveness of a screen-and-treat strategy was 54%, 90%, and 95% for a maximum acceptable cost-effectiveness threshold of €20,000, €50,000, and €80,000 per life-year gained, respectively. Higher albuminuria thresholds for screening and start of treatment further improved the cost-effectiveness but reduced the overall health gains achieved. Limiting screening to those subjects aged ≥50 and ≥60 years resulted in more favorable cost-effectiveness compared with population-based screening without age restriction. Conclusions: Our analyses suggest the potentially favorable cost-effectiveness of population-based screening for albuminuria in the general Dutch population. The results offer health care decision-makers new tools for considering actual implementation of such screening. [Copyright &y& Elsevier]

Abstract: Background: Tardive dyskinesia (TD) is a potentially irreversible consequence of long term treatment with antipsychotic drugs which is according to a well-known theory believed to be related to oxidative stress induced neurotoxicity. Dehydroepiandrosterone (DHEA) is an endogenous antioxidant with neuroprotective activity. The biosynthesis of DHEA depends upon the activity of cytochrome P450c17α (CYP17). The gene that encodes for CYP17 has a (T34C) single nucleotide polymorphism which enhances CYP17 transcription and expression. Objective: To test the hypothesis that carriership of a more active CYP17 variant would result in higher DHEA(S) levels and protect against neurotoxicity which results in orofaciolingual TD (TDof), limb-truncal TD (TDlt) or both (TDsum). Method: Tardive dyskinesia was assessed cross-sectionally in 146 Caucasian psychiatric inpatients from Siberia. Results: Patients who are carriers of the Cyp17 genotype CC have less chance of developing TD compared to patients who are carriers of the Cyp17 genotypes TC or TT (p<0.05). However, these carriers have significant lower circulating DHEAS levels compared to carriers of the Cyp17 genotypes TC and TT (p<0.05). Conversely, carriers of the CYP17 T-allele have significant elevated DHEAS levels. After correcting for gender and age no significant relationship between Cyp17 genotype CC, the T-allelle and the C-allele and the DHEAS concentration of patients was observed. Conclusions: Although an association between the CYP17 CC genotype and TD is indicated, our findings do not support the hypothesis that this is mediated through increased DHEA(S) levels. We believe that the relationship between this polymorphism and neuroprotective effects of steroids is more complex and cannot be elucidated without taking the posttranslational regulation of the enzyme into account. [Copyright &y& Elsevier]

Background: In the Netherlands, antihypertensive treatment for patients with mild hypertension is recommended if the 10-year cardiovascular disease (CVD) risk exceeds 20%. Recent evidence suggests that lifelong CVD risk estimates might be more informative than 10-year ones. In addition, the cost of antihypertensive treatment in the Netherlands has decreased during the last decade. Objective: The aim of this study is to estimate the cost-effectiveness of lowering systolic blood pressure (SBP) in patients ineligible for treatment in both a 10-year and a lifetime horizon. Methods: A Markov model was developed to assess the cost-effectiveness of SBP reduction compared with no reduction in patients with mild hypertension and low CVD risk. Modified SCORE (Systematic Coronary Risk Evaluation) risk estimates were used to predict fatal and nonfatal CVD events. We analyzed scenarios for different age groups, sexes, and SBP reductions. Specifically, SBP reductions due to hydrochlorothiazide (HCT) 25 mg and hypothetical reductions with HCT 12.5 mg-losartan 50 mg combination were assumed. Parameter uncertainty was assessed through a probabilistic sensitivity analysis. Results: In a 10-year horizon, in scenarios of SBP reduction with HCT 25 mg, the incremental cost-effectiveness ratio (ICER) estimates for men varied across different ages in the range of €6032 to €58,217 per life-year gained, whereas for women ICER estimates were in the range of €12,345 to €361,064 per life-year gained. In a lifetime horizon, the cost-effectiveness estimates were favorable for both sexes. In scenarios of hypothetical SBP reductions, more favorable ICER estimates compared with no reduction were found. A large uncertainty around the cost-effectiveness estimates was observed among all scenarios. Conclusion: Larger SBP reductions were found to be cost-effective in both a 10-year and lifetime horizon. These findings might call for more aggressive SBP reductions in patients with mild hypertension. However, a high level of uncertainty surrounds these cost-effectiveness estimates because they are based on CVD risk prediction modeling. [ABSTRACT FROM AUTHOR]