Pandurang M. Kulkarni

Skeletal Effects of Raloxifene After 8 Years: Results from the Continuing Outcomes Relevant to Evista (CORE) Study

In the CORE breast cancer trial of 4011 women continuing from MORE, the incidence of nonvertebral fractures at 8 years was similar between placebo and raloxifene 60 mg/day. CORE had limitations for assessing fracture risk. In a subset of 386 women, 7 years of raloxifene treatment significantly increased lumbar spine and femoral neck BMD compared from the baseline of MORE.

Medication nonadherence and treatment outcome in patients with schizophrenia or schizoaffective disorder with suboptimal prior response.

OBJECTIVE To examine the impact of medication nonadherence on treatment outcome in schizophrenia and potential risk factors for nonadherence. METHOD A post hoc analysis of a randomized, double-blind, 8-week, fixed-dose study comparing olanzapine 10, 20, and 40 mg/day for patients with schizophrenia or schizoaffective disorder (DSM-IV criteria) with suboptimal response to current treatment (N = 599) was conducted between September 12, 2003, and November 3, 2005, at 55 study centers in the United States. Nonadherence was defined as not taking medication as prescribed based on daily pill counts. Because there was no significant difference in nonadherence between dose groups, effects of nonadherence on efficacy and safety outcomes were examined using all 3 groups combined. Baseline demographics and symptom severity were investigated as potential risk factors for nonadherence. RESULTS During the 8-week study, 34.5% of patients were nonadherent at least once. Nonadherent patients had significantly less improvement compared to adherent patients as measured by change in Positive and Negative Syndrome Scale total score (-22.57 vs. -26.84, p = .002). Longer duration of nonadherence was associated with reduced likelihood of treatment response (odds ratio = 0.94, 95% CI = 0.90 to 0.99, p = .008). The early treatment discontinuation rate was higher in nonadherent compared to adherent patients (40.8% vs. 24.5%, p < .001). Adherent and nonadherent patients had comparable outcomes in most safety measures, except for weight change, for which adherent patients had greater weight gain than nonadherent patients (2.63 kg vs. 1.96 kg, p = .02). Greater depression severity at baseline (p = .01) and greater hostility level during the study were significant risk factors for nonadherence (p = .02). CONCLUSIONS Medication nonadherence had a significantly negative impact on treatment response, highlighting the importance of adherence to achieve satisfactory treatment outcome. Findings may also help clinicians identify patients at risk for nonadherence and utilize interventions to improve adherence. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00100776.

Risk-benefit profile for raloxifene: 4-year data from the multiple outcomes of Raloxifene Evaluation (MORE) randomized trial

Posthoc analysis of the MORE osteoporosis treatment trial assessed risk‐benefit profile of raloxifene in 7705 postmenopausal women. A major disease outcomes global index resulted in annual rates of 1.39% and 1.83% in the raloxifene and placebo groups, respectively (HR, 0.75; 95% CI, 0.62‐0.92), compatible with a favorable risk‐benefit profile for raloxifene for treating postmenopausal osteoporosis.

Comparison of Fracture, Cardiovascular Event, and Breast Cancer Rates at 3 Years in Postmenopausal Women with Osteoporosis

Objectives: To compare event rates for osteoporotic fractures, cardiovascular events, and breast cancer in postmenopausal women with osteoporosis.

Antiresorptive treatment of postmenopausal osteoporosis: review of randomized clinical studies and rationale for the Evista alendronate comparison (EVA) trial.

SUMMARY Standard pharmacological antiresorptive therapy for the prevention and/or treatment of postmenopausal osteoporosis now consists of four categories of drugs: estrogens, a selective estrogen receptor modulator (SERM), bisphosponates, and calcitonin. All of these drugs have been studied in randomized controlled trials, but meaningful comparisons of the efficacy of drugs have been difficult due to differences in baseline risks for fracture and differences in study design, including calcium and vitamin D supplementation, definition of fracture, and discontinuation rates. The current paper reviews results from pivotal studies of antiresorptive therapies with fracture as a primary endpoint, as well as head-to-head trials comparing these therapies using surrogate markers of fracture risk, and introduces the first head-to-head trial with fracture as a primary endpoint. The Evista* Alendronate Comparison (EVA) trial, a multi-center, double-blind, double-dummy, randomized trial with two active treatment arms is currently underway to compare directly the osteoporotic fracture risk reduction efficacy of raloxifene and alendronate in postmenopausal women with osteoporosis as defined by bone mineral density. The results from this trial will permit more informed judgment by practitioners and provider groups concerning the relative clinical utility of these two drugs. * Evista is a registered trade name of Eli Lilly and Company, Indianapolis, IN, USA

Evaluating and utilizing probability of study success in clinical development

Background Drug development has become increasingly costly, lengthy, and risky. The call for better decision making in research and development has never been stronger. Analytic tools that utilize available data can inform decision makers of the risks and benefits of various decisions, which could lead to better and more informed decisions. Purpose Through some real oncology examples, we will demonstrate how using available data to analytically evaluate probability of study success (PrSS) can lead to better decisions in clinical development. Methods The predictive power, or average conditional power, is used to quantify the PrSS. To calculate the probability, we follow a general two-step process: (1) use Bayesian modeling and appropriate assumptions to synthesize relevant data to derive the distribution of treatment effect and (2) evaluate the PrSS analytically or via trial simulation. Results We applied the procedure to several compounds in our oncology pipeline. The analysis informed decision making where PrSS was an important factor to consider. Limitations When modeling the treatment effect, we made certain assumptions, including how two drugs work together and exchangeable treatment effects across studies. Those assumptions are reasonable for our specific situations but may not generalize well. Conclusions From our experience, PrSS based on available data can help decision making in drug development, particularly the Go/No-Go decision after the proof of concept trial is completed. When applicable, we recommend this evaluation be regularly done in addition to the routine data analysis for clinical trials.

Vascular events in the Multiple Outcomes of Raloxifene Evaluation (MORE) trial : incidence, patient characteristics, and effect of raloxifene

Objective:To determine the incidence of arterial and venous thromboembolic (VTE) events, to determine the effect of raloxifene on the incidence of combined vascular (arterial and VTE) events, and to identify patient characteristics associated with these vascular events, in women participating in the MORE trial. Design:In a post hoc analysis using MORE data, arterial, VTE, and combined vascular event rates were compared between participants receiving placebo (n = 2,576) and those receiving 60 mg/dof raloxifene (n = 2,557). Baseline characteristics were compared between those who did and did not experience an arterial event. The same analysis was performed for VTE events. Results:Overall, during a mean follow-up time of 41 months, 178 women experienced an arterial event and 40 experienced a VTE event. In the placebo group, the incidence of arterial events exceeded VTE events by at least sevenfold. Raloxifene had no significant effect on the incidence of combined vascular events in the overall cohort (hazard ratio 0.95, 95% CI, 0.73-1.24). In a subset of women retrospectively determined to be at increased cardiovascular risk, raloxifene was associated with a lower incidence of combined vascular events (hazard ratio 0.63, 95% CI, 0.40-0.97). Baseline characteristics differed between those who did and those who did not experience an arterial event, but this was generally not the case for VTE events. Conclusions:Arterial events were more common than VTE events. The characteristics of women experiencing an arterial event differed from those experiencing a VTE event. Raloxifene had a neutral effect on the risk of combined vascular events in the overall population, and was associated with a reduced combined vascular event rate in women at increased cardiovascular risk. Additional studies are needed to confirm the effect of raloxifene on overall vascular outcomes.

Medication patterns and costs associated with olanzapine and other atypical antipsychotics in the treatment of bipolar disorder

ABSTRACT Objective: Atypical antipsychotics are playing an increasing role in the treatment of bipolar disorder. The objective of this study was to assess the medication treatment patterns and costs associated with different atypical antipsychotics. Methods: PharMetrics Integrated Database for medical and pharmacy claims was used to assess medication patterns and healthcare costs associated with atypical antipsychotics in the treatment of bipolar disorder. Patients who initiated on olanzapine, risperidone, quetiapine or ziprasidone as monotherapy or in combination with other bipolar medications between 01/2003 and 01/2004 were followed for 1 year. Pair-wise group comparisons were made between olanzapine and other atypical antipsychotics using Wilcoxon without adjustment, log linear regression model with adjustment, and propensity score-adjusted bootstrapping methods. Results: Among 1516 patients with bipolar disorder, olanzapine (n = 507, 51%) was significantly ( p < 0.01) more likely to be initiated as the mono-bipolar medication than risperidone (n = 424, 40%), quetiapine (n = 463, 36%) or ziprasidone (n = 122, 25%). Post-initiation, olanzapine was used as the mono-bipolar medication for significantly ( p < 0.01) more days (73.4) than risperidone (52.9), quetiapine (56.2) and ziprasidone (36.6). Annual healthcare costs incurred by patients with bipolar disorder varied from

Joint modeling of progression-free survival and overall survival by a Bayesian normal induced copula estimation model.

14 216 for risperidone,

Efficacy and safety of pemetrexed in elderly cancer patients: Results of an integrated analysis

15 208 for olanzapine,