Randomized, controlled, participant- and rater-blind trial of pharmacogenomic test-guided treatment versus treatment as usual for major depressive disorder.

BACKGROUND: Cohort and cost-effectiveness studies suggest that measuring variation in genes that influence metabolism of common drugs could improve antidepressant treatment outcomes. Prior randomized trials have yielded inconsistent results. METHOD: Multicenter randomized double-blind (subject and rater), controlled trial of pharmacogenomic testing among outpatients with nonpsychotic major depressive disorder. Study participants (n = 304) were randomized 1:1 to assay-guided treatment (AGT; N = 151) or treatment-as-usual (TAU; N = 153). Participants and raters were blinded to study arm; unblinded clinicians received results of a pharmacogenomic test and adjusted treatment in light of the test report. Primary outcome was change over 8 weeks in Hamilton Depression Rating Scale (SIGH-D-17). RESULTS: For the primary comparison of interest, change in SIGH-D-17, no significant difference was detected between AGT and TAU at Week 8 (p = .53). Rates of study completion also did not differ between the arms (AGT 92.7%, TAU 92.2% (χ2 = 0.03, df = 1, p = .86). Exploratory analyses suggested significantly fewer individuals experienced worsening of depressive symptoms following AGT, and that treatment concordant with assay results was associated with greater likelihood of remission. CONCLUSION: Pharmacogenomic testing using a panel of pharmacokinetic and pharmacodynamic variants was not associated with significant improvement in the primary efficacy outcome when providers were unconstrained by the assay results. Further investigation is needed to understand the discordance with cost-effectiveness results and among randomized trials.

Use of a consultation service following pharmacogenetic testing in psychiatry.

The emerging discipline of pharmacogenetics (PGx) has the goal of aiding the selection of effective therapies and personalized dosing, decreasing the likelihood of adverse drug reactions and optimizing resource utilization. Simultaneously, the rapid evolution of economically feasible genetic testing technologies has resulted in a raft of commercial entities that provide genetic data to providers for use with their complex patients. The adoption of pharmacogenomics in psychiatry is growing, but it is limited by several factors, including the limitless permutations of drugs, comorbid conditions and concomitant medications and provider understanding of phenomena such as phenoconversion. We established an expert PGx consultation service for psychiatric providers who utilize our commercial PGx assay. To date, this service has provided ∼16,000 consults with extremely high levels of satisfaction; in an anonymous survey, 96% of respondents reported a rating of "very helpful" or "extremely helpful".

Predicting drug-drug and drug-gene interactions in a community pharmacy population.

OBJECTIVES: Drug-drug interactions (DDIs) are among the most common causes of adverse drug reactions and are further complicated by genetic variants of drug-metabolizing enzymes. The aim of this study is to quantify and describe potential DDIs, drug-gene interactions (DGIs), and drug-drug-gene interactions (DDGIs) in a community-based population. STUDY DESIGN: This was an analysis of deidentified retail pharmacy prescription data for 4761 individuals. METHODS: Data were first assessed for DDIs, and individuals were stratified to a risk category using the logic of a commercially available digital DDGI tool. To calculate the frequency of potential DGIs and DDGIs, genotypes were imputed and randomly allocated to the cohort 100 times via Monte Carlo simulation according to each variant's frequency in the general population. RESULTS: The probability of a DDI of any impact was 26.0% and increased to 49.6% (95% CI, 48.4%-50.7%) when drug-metabolizing phenotypes were ascribed according to the distribution of variants of 11 genes as found in a Caucasian population. There was a 7.8% probability of major DDIs, which increased to a 10.1% (95% CI, 9.5%-10.8%) probability with the addition of genetic contributions. The probability of DDGIs of any impact was correlated with the number of medications. Antidepressants, antiemetics, blood products and modifiers, analgesics, and antipsychotics had the highest probability of DDGIs. CONCLUSIONS: The probability of drug interaction risk increased when phenotypes associated with genetic polymorphisms were attributed to the population. These data suggest that pharmacogenomic assessment may be useful in predicting drug interactions and severity when evaluating patient medication profiles.

Anidulafungin versus fluconazole for invasive candidiasis.

BACKGROUND: Anidulafungin, a new echinocandin, has potent activity against candida species. We compared anidulafungin with fluconazole in a randomized, double-blind, noninferiority trial of treatment for invasive candidiasis. METHODS: Adults with invasive candidiasis were randomly assigned to receive either intravenous anidulafungin or intravenous fluconazole. All patients could receive oral fluconazole after 10 days of intravenous therapy. The primary efficacy analysis assessed the global response (clinical and microbiologic) at the end of intravenous therapy in patients who had a positive baseline culture. Efficacy was also assessed at other time points. RESULTS: Eighty-nine percent of the 245 patients in the primary analysis had candidemia only. Candida albicans was isolated in 62% of the 245 patients. In vitro fluconazole resistance was infrequent. Most of the patients (97%) did not have neutropenia. At the end of intravenous therapy, treatment was successful in 75.6% of patients treated with anidulafungin, as compared with 60.2% of those treated with fluconazole (difference, 15.4 percentage points; 95% confidence interval [CI], 3.9 to 27.0). The results were similar for other efficacy end points. The statistical analyses failed to show a "center effect"; when data from the site enrolling the largest number of patients were removed, success rates at the end of intravenous therapy were 73.2% in the anidulafungin group and 61.1% in the fluconazole group (difference, 12.1 percentage points; 95% CI, -1.1 to 25.3). The frequency and types of adverse events were similar in the two groups. The rate of death from all causes was 31% in the fluconazole group and 23% in the anidulafungin group (P=0.13). CONCLUSIONS: Anidulafungin was shown to be noninferior to fluconazole in the treatment of invasive candidiasis. (ClinicalTrials.gov number, NCT00056368 [ClinicalTrials.gov]).

Economic effectiveness of disease management programs: a meta-analysis.

The economic effectiveness of disease management programs, which are designed to improve the clinical and economic outcomes for chronically ill individuals, has been evaluated extensively. A literature search was performed with MEDLINE and other published sources for the period covering January 1995 to September 2003. The search was limited to empirical articles that measured the direct economic outcomes for asthma, diabetes, and heart disease management programs. Of the 360 articles and presentations evaluated, only 67 met the selection criteria for meta-analysis, which included 32,041 subjects. Although some studies contained multiple measurements of direct economic outcomes, only one average effect size per study was included in the meta-analysis. Based on the studies included in the research, a meta-analysis provided a statistically significant answer to the question of whether disease management programs are economically effective. The magnitude of the observed average effect size for equally weighted studies was 0.311 (95% CI = 0.272-0.350). Statistically significant differences of effect sizes by study design, disease type and intensity of disease management program interventions were not found after a moderating variable, disease severity, was taken into consideration. The results suggest that disease management programs are more effective economically with severely ill enrollees and that chronic disease program interventions are most effective when coordinated with the overall level of disease severity. The findings can be generalized, which may assist health care policy makers and practitioners in addressing the issue of providing economically effective care for the growing number of individuals with chronic illness.

A randomized, double-blind trial of anidulafungin versus fluconazole for the treatment of esophageal candidiasis.

Anidulafungin is a novel antifungal agent of the echinocandin class. This randomized, double-blind, double-dummy study compared the efficacy and safety of intravenous anidulafungin to that of oral fluconazole in 601 patients with endoscopically and microbiologically documented esophageal candidiasis. Patients received intravenous anidulafungin (100 mg on day 1, followed by 50 mg per day) or oral fluconazole (200 mg on day 1, followed by 100 mg per day) for 7 days beyond resolution of symptoms (range, 14-21 days). At the end of therapy, the rate of endoscopic success for anidulafungin (242 [97.2%] of 249 treated patients) was found to be statistically noninferior to that for fluconazole (252 [98.8%] of 255 treated patients; treatment difference, -1.6%; 95% confidence interval, -4.1 to 0.8). The safety profile of anidulafungin was similar to that of fluconazole; treatment-related adverse events occurred in 9.3% and 12.0% of patients, respectively. Laboratory parameters were similar between treatment arms. Anidulafungin is as safe and effective as oral fluconazole for the treatment of esophageal candidiasis, when assessed at the completion of therapy.

A phase 3 trial of the efficacy and safety of oral recombinant calcitonin: the Oral Calcitonin in Postmenopausal Osteoporosis (ORACAL) trial.

The Oral Calcitonin in Postmenopausal Osteoporosis (ORACAL) study was a randomized, double-blind, double-dummy, active- and placebo-controlled, multiple-dose, phase 3 study to assess the efficacy and safety of oral recombinant calcitonin for treatment of postmenopausal osteoporosis. A total of 565 women age 46 to 86 (mean 66.5) years were randomized (4:3:2) to receive oral recombinant salmon calcitonin (rsCT) tablets (0.2 mg/d) plus placebo nasal spray, synthetic salmon calcitonin (ssCT) nasal spray (200 IU/d) plus placebo tablets, or placebo (placebo tablets plus placebo nasal spray), respectively for 48 weeks. All women received calcium (≥1000 mg/d) and vitamin D (800 IU/d). Women randomized to oral rsCT had a mean ± SD percent increase from baseline in lumbar spine bone mineral density (BMD) (1.5% ± 3.2%) that was greater than those randomized to ssCT nasal spray (0.78% ± 2.9%) or placebo (0.5% ± 3.2%). Lumbar spine BMD change in those receiving nasal calcitonin did not differ from placebo. Oral rsCT treatment also resulted in greater improvements in trochanteric and total proximal femur BMD than ssCT nasal spray. Reductions in bone resorption markers with oral rsCT were greater than those observed in ssCT nasal spray or placebo recipients. Approximately 80% of subjects in each treatment group experienced an adverse event, the majority of which were mild or moderate in intensity. Gastrointestinal system adverse events were reported by nearly one-half of women in all treatment groups and were the principal reason for premature withdrawals. Less than 10% of women experienced a serious adverse event and no deaths occurred. Overall, oral rsCT was superior to nasal ssCT and placebo for increasing BMD and reducing bone turnover. Oral rsCT was safe and as well tolerated as ssCT nasal spray or placebo. Oral calcitonin may provide an additional treatment alternative for women with postmenopausal osteoporosis.

Phase 2, randomized, dose-ranging study evaluating the safety and efficacy of anidulafungin in invasive candidiasis and candidemia.

This study evaluated the safety and efficacy of anidulafungin, a novel echinocandin, in patients with invasive candidiasis, including candidemia. A total of 123 eligible patients were randomized to one of three intravenous regimens, 50, 75, or 100 mg once daily. Treatment continued for 2 weeks beyond resolution or improvement of signs and symptoms. The primary efficacy criterion was a successful global response rate (i.e., clinical and microbiological success) in the evaluable population at the follow-up (FU) visit, 2 weeks after end of therapy (EOT). One hundred twenty (120) patients received at least one dose of anidulafungin; 68 were evaluable. Review of adverse events and laboratory data indicated no dose response for safety parameters. Non-albicans Candida species accounted for approximately one-half of all isolates. Success rates at EOT were 84, 90, and 89% in the 50-, 75-, and 100-mg groups, respectively. At FU, the success rates were 72, 85, and 83%. Phase 3 studies of anidulafungin for the treatment of invasive candidiasis and candidemia are warranted.

Effect of maternal antibody on immunogenicity of hepatitis A vaccine in infants.

OBJECTIVE: To determine the effect of maternal antibody on hepatitis A vaccine immunogenicity in infants. Study design Infants of mothers negative for antibody to hepatitis A virus (anti-HAV; group 1) were administered hepatitis A vaccine at 2, 4, and 6 months of age, and infants of anti-HAV-positive mothers were randomized to receive either hepatitis A vaccine (group 2) or hepatitis B vaccine (group 3) on the same schedule. Group 3 infants subsequently received hepatitis A vaccine at 8 and 10 months of age. RESULTS: At 15 months of age, 100% of infants in group 1, 93% in group 2, and 92% in group 3 had protective levels of antibody. However, there were significant differences in the geometric mean concentration (GMC) of anti-HAV between groups. Group 1 GMC was 231 mIU/mL, compared with 85 mIU/mL for group 2 and 84 mIU/mL for group 3 (P<.001, group 1 vs group 3). CONCLUSIONS: Passively acquired maternal anti-HAV resulted in a significantly lower final antibody response when infants were administered hepatitis A vaccine at 2, 4, and 6 months of age or at 8 and 10 months of age.