A phase i dose escalation study to determine the optimal biological dose of irosustat, an oral steroid sulfatase inhibitor, in postmenopausal women with estrogen receptor-positive breast cancer

Steroid sulfatase (STS) inhibition may have a therapeutic role in suppression of endocrine-responsive breast cancer. This study aimed to determine the optimal biological dose and recommended dose (RD) of the STS inhibitor irosustat. A three-part, open-label, multicenter, dose escalation study of irosustat in estrogen receptor-positive breast cancer patients involved administration of a single dose of irosustat with a 7-day observation period; followed by a daily oral dose of irosustat for 28 days; and an extension phase, in which the daily oral dose of irosustat was continued at the discretion of the investigator and as long as the patient was benefitting from the treatment. Five doses of irosustat were tested (1, 5, 20, 40, and 80 mg) in 50 patients. After 28 days of daily administration of irosustat, all the evaluated patients in the 5, 20, 40, and 80 mg cohorts achieved ≥95 % STS inhibition in peripheral blood mononuclear cells and corresponding endocrine suppression. The maximum tolerated dose was not reached, and the 40 mg dose was established as the RD. The median time to disease progression in the 40 mg cohort was 11.2 weeks. Disease stabilization was achieved in 10 % of patients potentially indicative of drug activity. Dry skin was the most frequent adverse event. The RD of irosustat is 40 mg. Disease stabilization occurred in 10 % of this heavily pretreated patient population. A larger study is required to define an accurate response rate to irosustat as a single agent and whether co-administration with an aromatase inhibitor is needed. © 2013 Springer Science+Business Media New York.SCOPUS: ar.jinfo:eu-repo/semantics/publishe

Assessment of Bowel Preparation Using Low-Volume Sulphate-Based Preparations in Comparison with Macrogols: A Multicenter, Randomized, Comparative Clinical Study of the 3rd Phase

Oral sulphate solution (OSS: sodium sulphate, potassium sulphate and magnesium sulphate) is a low-volume osmotic agent for cleansing the intestines.Aim: in a multicentre, prospective, randomized, 3rd phase study with two parallel groups, the effectiveness, safety and tolerability of OSS was evaluated in comparison with Macrogol 4000 with electrolytes (a reference preparation for bowel cleansing in Russia) in adult patients who were scheduled for routine diagnostic colonoscopy.Methods. This study was conducted in three Russian research centres during the March–December, 2015 period. Men and women over the age of 18 scheduled to undergo routine diagnostic colonoscopy were randomly assigned either to the OSS group or to the Macrogol group with a fractional use mode before the colonoscopy. The colonoscopy researchers were not aware of which preparation had been taken by the patients. Anonymized video records were centrally analysed by three experts. The primary end point was the proportion of patients with a successful bowel preparation for colonoscopy ≥6 points, as determined by the Boston Bowel Preparation Scale of quality assessment (BBPS scale).Results. 296 patients were randomized in the study (147 patients were treated with OSS, 149 patients received Macrogol); 294 participants were included in the Intention to Treat population (ITT-population), and 274 participants were included in the population of patients who completed the study according to the protocol (Per-Protocol; PP-population) (139 patients received OSS, 135 patients received Macrogol). The proportion of patients with a successful bowel preparation (BBPS ≥6 scores) was high in both groups (OSS [PP-population]: 97.2 % (95 % confidence interval [CI] 89.5–99.3), Macrogol [PP-population]: 97.7 % (95 % CI: 90.7–99.4)). The corrected difference between the groups was -0.5 % (95 % CI: -4.2–3.3), thereby demonstrating “no less effective” of OSS as compared to Macrogol. Compliance with the drug use regime was higher in the OSS group than in the Macrogol group (95.7 % versus 82.3 %, respectively, p-value = 0.0011, ITT-population).The most common symptom reported in patients was nausea (27.9 % in the OSS group and 12.9 % in the Macrogol group). The proportion of patients who developed nausea was significantly higher in the OSS group than in the Macrogol group (25.2 % compared with 10.2 % when taking the first dose of the preparation (p = 0.0008) and 19.7 % compared with 6.8 % when taking the second dose of the preparation (p = 0.0016)). Differences in other symptoms (bloating, abdominal pain or abdominal discomfort) between the groups were not significant, with the severity of symptoms being generally mild. The safety profile of the investigated preparations in patients with inflammatory bowel disease (IBD) in remission did not differ from that in the general patient population.The differences in terms of secondary endpoints were not identified, including BBPS assessment for different sections of the colon, the level of polyp detection, the duration and completeness of colonoscopy, and the investigator’s satisfaction with the procedure. The analysis by subgroups also did not reveal any significant differences.Conclusion. In this study, the “not less effectiveness” of the sulphate solution was demonstrated as compared to Macrogol in a fractional use mode. Both preparations were well tolerated. Despite the higher incidence of nausea in the OSS group, the patients showed significantly higher compliance with the OSS mode as compared to that of Macrogol.This study is registered with the ClinicalTrials.gov Registry of Clinical Trials, No. NCT02321462

Assessment of Bowel Preparation Using Low-Volume Sulphate-Based Preparations in Comparison with Macrogols: A Multicenter, Randomized, Comparative Clinical Study of the 3rd Phase

Oral sulphate solution (OSS: sodium sulphate, potassium sulphate and magnesium sulphate) is a low-volume osmotic agent for cleansing the intestines.Aim: in a multicentre, prospective, randomized, 3rd phase study with two parallel groups, the effectiveness, safety and tolerability of OSS was evaluated in comparison with Macrogol 4000 with electrolytes (a reference preparation for bowel cleansing in Russia) in adult patients who were scheduled for routine diagnostic colonoscopy.Methods. This study was conducted in three Russian research centres during the March–December, 2015 period. Men and women over the age of 18 scheduled to undergo routine diagnostic colonoscopy were randomly assigned either to the OSS group or to the Macrogol group with a fractional use mode before the colonoscopy. The colonoscopy researchers were not aware of which preparation had been taken by the patients. Anonymized video records were centrally analysed by three experts. The primary end point was the proportion of patients with a successful bowel preparation for colonoscopy ≥6 points, as determined by the Boston Bowel Preparation Scale of quality assessment (BBPS scale).Results. 296 patients were randomized in the study (147 patients were treated with OSS, 149 patients received Macrogol); 294 participants were included in the Intention to Treat population (ITT-population), and 274 participants were included in the population of patients who completed the study according to the protocol (Per-Protocol; PP-population) (139 patients received OSS, 135 patients received Macrogol). The proportion of patients with a successful bowel preparation (BBPS ≥6 scores) was high in both groups (OSS [PP-population]: 97.2 % (95 % confidence interval [CI] 89.5–99.3), Macrogol [PP-population]: 97.7 % (95 % CI: 90.7–99.4)). The corrected difference between the groups was -0.5 % (95 % CI: -4.2–3.3), thereby demonstrating “no less effective” of OSS as compared to Macrogol. Compliance with the drug use regime was higher in the OSS group than in the Macrogol group (95.7 % versus 82.3 %, respectively, p-value = 0.0011, ITT-population).The most common symptom reported in patients was nausea (27.9 % in the OSS group and 12.9 % in the Macrogol group). The proportion of patients who developed nausea was significantly higher in the OSS group than in the Macrogol group (25.2 % compared with 10.2 % when taking the first dose of the preparation (p = 0.0008) and 19.7 % compared with 6.8 % when taking the second dose of the preparation (p = 0.0016)). Differences in other symptoms (bloating, abdominal pain or abdominal discomfort) between the groups were not significant, with the severity of symptoms being generally mild. The safety profile of the investigated preparations in patients with inflammatory bowel disease (IBD) in remission did not differ from that in the general patient population.The differences in terms of secondary endpoints were not identified, including BBPS assessment for different sections of the colon, the level of polyp detection, the duration and completeness of colonoscopy, and the investigator’s satisfaction with the procedure. The analysis by subgroups also did not reveal any significant differences.Conclusion. In this study, the “not less effectiveness” of the sulphate solution was demonstrated as compared to Macrogol in a fractional use mode. Both preparations were well tolerated. Despite the higher incidence of nausea in the OSS group, the patients showed significantly higher compliance with the OSS mode as compared to that of Macrogol.This study is registered with the ClinicalTrials.gov Registry of Clinical Trials, No. NCT02321462

Lipoprotein(a) and Benefit of PCSK9 Inhibition in Patients With Nominally Controlled LDL Cholesterol

International audienceBackground: Guidelines recommend nonstatin lipid-lowering agents in patients at very high risk for major adverse cardiovascular events (MACE) if low-density lipoprotein cholesterol (LDL-C) remains ≥70 mg/dL on maximum tolerated statin treatment. It is uncertain if this approach benefits patients with LDL-C near 70 mg/dL. Lipoprotein(a) levels may influence residual risk.Objectives: In a post hoc analysis of the ODYSSEY Outcomes (Evaluation of Cardiovascular Outcomes After an Acute Coronary Syndrome During Treatment With Alirocumab) trial, the authors evaluated the benefit of adding the proprotein subtilisin/kexin type 9 inhibitor alirocumab to optimized statin treatment in patients with LDL-C levels near 70 mg/dL. Effects were evaluated according to concurrent lipoprotein(a) levels.Methods: ODYSSEY Outcomes compared alirocumab with placebo in 18,924 patients with recent acute coronary syndromes receiving optimized statin treatment. In 4,351 patients (23.0%), screening or randomization LDL-C was 13.7 mg/dL or ≤13.7 mg/dL; corresponding adjusted treatment hazard ratios were 0.82 (95% CI: 0.72-0.92) and 0.89 (95% CI: 0.75-1.06), with Pinteraction = 0.43.Conclusions: In patients with recent acute coronary syndromes and LDL-C near 70 mg/dL on optimized statin therapy, proprotein subtilisin/kexin type 9 inhibition provides incremental clinical benefit only when lipoprotein(a) concentration is at least mildly elevated. (ODYSSEY Outcomes: Evaluation of Cardiovascular Outcomes After an Acute Coronary Syndrome During Treatment With Alirocumab; NCT01663402)