Safety and pharmacodynamic dose response of short-term prednisone in healthy adult subjects: a dose ranging, randomized, placebo-controlled, crossover study.

BACKGROUND: Glucocorticoids (GCs), such as prednisone, are the standard of care for several inflammatory and immunologically mediated diseases, but their chronic systemic administration is severely limited by serious adverse effects that are both dose and time dependent. Short-term treatment (7-14 days) with oral prednisone is used for many acute inflammatory and allergic conditions. This study was conducted to characterize the safety and pharmacodynamic (PD) dose-response of a 7-day course of oral prednisone on biomarkers of GC receptor agonism. METHODS: In this randomized, single-blind, placebo-controlled, crossover study (A9001309), 37 healthy subjects received placebo or a prednisone dose from 2.5-60 mg daily over 7 days in each of three treatment periods. White blood cell counts and plasma samples for measuring cortisol, osteocalcin and procollagen type 1 N-propeptide (P1NP) were obtained at 2, 4, 8, and 12 h post-dose on Day 1, immediately prior to dosing on Days 1, 2, and 4, and at nominal dosing time on Days 0 and 8. Urine samples for urinary N-terminal cross-linked telopeptide of type 1 collagen (uNTX) were collected on Days 0, 1, 2, 4, and 8. Serum samples for adiponectin were obtained prior to dosing on days 0, 1, 4 and 8. RESULTS: Daily doses of prednisone up to 60 mg resulted in dose- and time-dependent decreases in plasma osteocalcin, plasma P1NP, serum cortisol, and absolute blood eosinophil counts. Absolute blood neutrophil counts increased, while blood lymphocyte counts rebounded to an increased level following an initial rapid decrease after dosing. An increase was observed for uNTX and adiponectin. The incidence of adverse effects with prednisone was not dose related, and nervous system disorders, mainly headache, were the most frequently reported adverse effects. CONCLUSIONS: This characterization provides important and relevant information on safety and PD responses of short-term prednisone dosing over the commonly-used clinical dose range, and also provides a reference for early clinical development of dissociated agents targeting a differentiated PD profile. TRIAL REGISTRATION NUMBER: NCT02767089 (retrospectively registered: 21 April 2016).

Three-year outcome of the Halt trial: a prospective analysis of radiofrequency volumetric thermal ablation of myomas.

STUDY OBJECTIVE: To analyze the clinical success of radiofrequency volumetric thermal ablation (RFVTA) at 3-year follow-up in terms of subject responses to validated questionnaires and surgical repeat intervention to treat myomas. DESIGN: Prospective follow-up of patients for 36 months after treatment in a multicenter international trial of outpatient, laparoscopic ultrasound-guided RFVTA of symptomatic uterine myomas (Canadian Task Force classification II-1). SETTING: University hospitals and private surgical centers. PATIENTS: One hundred thirty-five premenopausal women (mean [SD] age, 42.5 [4.6] years; body mass index, 30.5 [6.1]) with symptomatic uterine myomas and objectively confirmed heavy menstrual bleeding (≥ 160 to ≤ 500 mL). INTERVENTIONS: Laparoscopic ultrasound-guided RFVTA. MEASUREMENTS AND MAIN RESULTS: One hundred four participants were followed prospectively for 36 months after treatment of myomas via RFVTA. For 104 evaluable participants with 36-month data, change in mean (SD) symptom severity from baseline (60.2 [18.8]) to 36 months was -32.6 (95% confidence interval, -37.5 to -27.8; p < .001). Health-related quality of life also was improved, from the baseline value of 39.2 (19.2) to 38.6 (95% confidence interval, 33.3 to 43.9; p < .001) at 36 months. Patient-reported Uterine Fibroid Symptom and Health-Related Quality of Life questionnaire subscores demonstrated statistically significant improvement from baseline to 36 months in all categories (Concern, Activities, Energy/Mood, Control, Self-consciousness, and Sexual Function) (p < .001). For the 104 participants with 36-month data, mean state of health scores (EuroQOL-5D Health State Index) improved from a baseline value of 71.0 (19.3) to 86.2 (11.7) at 36 months. The cumulative repeat intervention rate of 11% (14 of 135 participants) at 36 months was well below the possible 25% maximum expected at the beginning of the trial. CONCLUSION: RFVTA of uterine myomas resulted in sustained relief from myoma symptoms and continued improvement in health-related quality of life through 36 months after ablation. The low repeat intervention data through 36 months is a positive outcome for patient well-being.

Sensitivity of myoma imaging using laparoscopic ultrasound compared with magnetic resonance imaging and transvaginal ultrasound.

STUDY OBJECTIVE: To determine the efficacy of laparoscopic ultrasound (LUS) as compared with contrast-enhanced magnetic resonance imaging (CE-MRI) and transvaginal ultrasound (TVUS) in detection of uterine myomas. DESIGN: Retrospective study of imaging methods used in a trial of LUS-guided radiofrequency volumetric thermal ablation in women with symptomatic myomas (Canadian Task Force classification II-2). SETTING: Eleven medical university or private outpatient surgery clinics in the United States (nine sites) and Latin America (two sites). PATIENTS: One hundred thirty-five women with symptomatic myomas and objectively confirmed moderate to severe heavy menstrual bleeding. INTERVENTIONS: LUS-guided radiofrequency volumetric thermal ablation of myomas. MEASUREMENTS AND MAIN RESULTS: Preoperative TVUS scans and CE-MRIs were read at each site, and all CE-MRIs were read by a central reader. LUS-guided scans were obtained intraoperatively by each surgeon by mapping the uterus just before radiofrequency volumetric thermal ablation. The imaging methods and their yields in terms of number of myomas found per subject were as follows: TVUS, 403 myomas (mean [SD] 3 [1.8]; range, 1-8); site CE-MRI, 562 myomas (4.2 [3.8]; range, 1-18); central reader, 619 myomas (4.6 [3.7]; range, 0-20); and LUS, 818 myomas (6.1 [4.9]; range, 1-29) (p < .001). LUS was superior to TVUS, CE-MRI, and the central reader for detection of small (≤1 cm(3)) myomas. Most imaged myomas were intramural: 197 (50.9%) by TVUS, 298 (55.5%) by site CE-MRI, 290 (48.7%) by the central reader, and 386 (48.5%) by LUS. CONCLUSION: Compared with CE-MRI and TVUS, LUS demonstrates the most myomas, regardless of size or type.

Using graphical displays of exact overall significance levels as a guideline for choosing a significance level for pairwise comparisons of a dichotomous variable.

Exact overall significance levels for selected sample sizes and response probabilities are graphically displayed when a dichotomous variable is compared between a placebo and two or more active treatments. A Z-statistic with a pooled variance estimator is used as the test statistic and critical values are based on the (1 - alpha/2)th percentile of the standard normal distribution. These figures are used as a simple guideline for choosing significance levels that achieve a desired overall significance level. If an overall significance level of 0.05 is desired when comparing a placebo to two, three, or four active treatments, the recommended significance levels to be used for each of the two, three, or four pairwise comparisons are 0.027, 0.019, or 0.015. If an overall significance level of 0.10 is desired, the corresponding recommended significance levels are 0.055, 0.039, or 0.031.

Congestive heart failure in patients treated with doxorubicin: a retrospective analysis of three trials.

BACKGROUND: Doxorubicin is a highly effective and widely used cytotoxic agent with application that is limited by cardiotoxicity related to the cumulative dose of the drug. A large-scale study that retrospectively evaluated the cardiotoxicity of doxorubicin reported that an estimated 7% of patients developed doxorubicin-related congestive heart failure (CHF) after a cumulative dose of 550 mg/m(2). To assess whether this estimate is reflective of the incidence in the broader clinical oncology setting, the authors evaluated data from three prospective studies to determine both the incidence of doxorubicin-related CHF and the accumulated dose of doxorubicin at which CHF occurs. METHODS: A group of 630 patients who were randomized to a doxorubicin-plus-placebo arm of three Phase III studies, two studies in patients with breast carcinoma and one study in patients with small cell lung carcinoma, were included in the analysis. RESULTS: Thirty-two of 630 patients had a diagnosis of CHF. Analysis indicated that an estimated cumulative 26% of patients would experience doxorubicin-related CHF at a cumulative dose of 550 mg/m(2). Age appeared to be an important risk factor for doxorubicin-related CHF after a cumulative dose of 400 mg/m(2), with older patients (age > 65 years) showing a greater incidence of CHF compared with younger patients (age < or = 65 years). In addition, > 50% of the patients who experienced doxorubicin-related CHF had a reduction < 30% in left ventricular ejection fraction (LVEF) while they were on study. CONCLUSIONS: Doxorubicin-related CHF occurs with greater frequency and at a lower cumulative dose than previously reported. These findings further indicate that LVEF is not an accurate predictor of CHF in patients who receive doxorubicin.