Terms Of Secondary Endpoints Research Articles

Ticagrelor or prasugrel in patients with acute coronary syndrome and prior myocardial infarction

Abstract Objectives To investigate the efficacy and safety of ticagrelor versus prasugrel in patients with acute coronary syndrome (ACS) and prior myocardial infarction (MI). Background The efficacy and safety of ticagrelor versus prasugrel in ACS patients with prior MI remains unstudied. Methods Patients with ACS scheduled for an invasive strategy and randomized to ticagrelor or prasugrel in the ISAR-REACT 5 trial with available information concerning prior MI were included in the present analysis. The primary endpoint was the composite of all-cause death, myocardial infarction, or stroke; the secondary endpoint was Bleeding Academic Research Consortium (BARC) type 3 to 5 bleeding. Endpoints were assessed 12 months after randomization. Results A total of 4,015 patients were included in this analysis (prior MI= 631 patients; no prior MI = 3,384 patients). As compared to patients without prior MI, the primary endpoint occurred more frequently in patients with prior MI (12.6% vs. 7.2%; hazard ratio [HR] = 1.78, 95% confidence interval [CI] 1.38–2.29; p= <0.001) without significant difference in terms of secondary endpoint between groups (5.8% vs. 5.7%; HR=1.02 [0.71–1.45]; p=0.921). Patients with prior MI randomized to ticagrelor versus prasugrel displayed higher risk for primary (HR=1.62 [1.03–2.55]) but not secondary endpoint (HR=1.28 [0.56–2.91]). Patients without prior MI randomized to ticagrelor or prasugrel displayed no significant difference in terms of primary (HR=1.28 [0.99–1.65]) or secondary endpoints (HR=1.13 [0.82–1.55]). There was no treatment assignment-by-prior MI status interaction with respect to the primary (p for interaction = 0.373) and the secondary (p for interaction= 0.786) endpoints. Conclusions Patients with ACS and prior MI are at higher risk for recurrent ischemic but not bleeding events. The history of MI does not affect the relative efficacy and safety of ticagrelor versus prasugrel in patients with ACS. Funding Acknowledgement Type of funding sources: Public grant(s) – National budget only. Main funding source(s): German Center for Cardiovascular Research (DZHK)Deutsches Herzzentrum München

Quality of life associated with orthotopic neobladder and ileal conduit in women: A multicentric cross-sectional study

To compare quality of life and functional outcomes associated with orthotopic neobladder (ONB) and ileal conduit (IC) after anterior pelvic exenteration for bladder cancer in women, through a multicentric cross-sectional study. All women who have undergone an anterior pelvic exenteration associated with ONB or IC for a bladder cancer between January 2004 and December 2014 within the three participating university hospital centers and that were still alive in February 2016 were included. Three distinct auto-administered questionnaires were submitted to the patients: the EORTC QLQ-C30, the EORTC QLQ-BLmi30 and the SF-12. Comparison of response to these questionnaires between women with ONB and those with IC were studied with Mann-Whitney U tests, with a statistically significant P-value set at<0.05. The primary endpoint was the "global health status" sub-score extracted from the EORTC QLQ-C30 questionnaire. The secondary endpoints were the functional sub-scores and symptoms sub-scores obtained with the EORTC QLQ-C30 questionnaire as well as the sub-scores obtained with the EORTC QLQ-BLmi30 and the SF-12 questionnaires. Forty women were included in the study (17 ONB, 23 IC). The primary endpoint was comparable between the ONB and IC women (83.3 vs. 66.7 P=0.22). Similarly, no significant statistical difference could be pointed between the ONB and IC women in terms of secondary endpoints. The present study did not report any significance difference in terms of quality of life and functional outcomes between women with ONB and those with IC after pelvic exenteration for bladder cancer. 3.

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 withinflammatory 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.Conflict of interest: this study was sponsored by Ipsen Pharma.Acknowledgements: the authors express their sincere gratitude to all the patients who participated in the study, as well as to specialists having provided medical care for the patients, researchers and employees of the participant research centres. The authors also express their appreciation to Olga Kapitonova, an employee of the Almedis company (Moscow, Russia) for her assistance in compiling medical texts, which activity was carried out under the financial support of the Ipsen company (Moscow, Russia) in accordance with the Good Publication Practice (GPP).

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 theBoston 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 theIntention to Treat population(ITT-population), and 274 participants were included in thepopulation 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 withinflammatory 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.

Comparison of hepatic arterial infusion chemotherapy between 5-fluorouracil-based continuous infusion chemotherapy and low-dose cisplatin monotherapy for advanced hepatocellular carcinoma.

The aim of this study is to compare the efficacy and safety of hepatic arterial infusion chemotherapy (HAIC) between 5-fluorouracil (5-FU)-based continuous infusion chemotherapy and low-dose cisplatin (CDDP) monotherapy in patients with advanced hepatocellular carcinoma (HCC). Patients were grouped according to HAIC regimen (5-FU group, n = 317/CDDP group, n = 66). A two-to-one match was created using propensity score analysis (5-FU group, n = 102/CDDP group, n = 51). After matching, response rate (RR) and adverse events as primary end-points, and survival and progression-free survival as secondary end-points, were analyzed. In the analysis of primary end-points, the RR in the 5-FU group was significantly higher than in the CDDP group (32.4% vs. 15.7%, P = 0.033). In patients with a Child-Pugh (CP) score of 5-7, the RR in the 5-FU group was significantly higher than that in the CDDP group (36.1% vs. 15.4%, P = 0.020). In those with a CP score of 8-9, there was no significant difference in RR between the two groups (15.8% vs. 16.6%, P = 1.000). The reservoir system-related complications were 9.8% in the 5-FU group, and there was no significant difference in the incidence of grade 3/4 adverse events between the two matched groups (P > 0.05). In terms of secondary end-points, the median survival time was 9.1 and 8.7months for the 5-FU and CDDP groups, respectively (P = 0.4917). Progression-free survival was 3.9months for the 5-FU group and 4.9months for the CDDP group (P = 0.4). 5-Fluorouracil-based continuous infusion chemotherapy could be suitable for advanced HCC patients with a CP score of 5-7 considering the treatment response.

Value of Cardiac Troponin and sPESI in Treatment of Pulmonary Thromboembolism at Outpatient Setting.

Currently, guidelines do not recommend any standard approach for treatment of pulmonary thromboembolism (PTE) at outpatient setting. We investigated the efficacy and safety of a 90-day anticoagulant treatment of outpatients diagnosed with PTE who had negative troponin levels and low-risk simplified pulmonary embolism severity index (sPESI) at presentation. This prospective cohort study included a total of 206 patients with objectively confirmed acute symptomatic PTE. Any troponin negative (cTn-) and low sPESI patients (as classified Group-1) were treated in outpatient setting. The primary endpoint was all-cause mortality during the first 90 days, and the secondary endpoint included non-fatal symptomatic recurrent PTE or non-fatal major bleeding. Presence of cancer was excluded from sPESI score. Fifty-two of 206 patients were eligible for had Group-1, and 31 were treated at outpatients settings. The 90-day all-cause mortality rate was 3.2 % among patients who received outpatient treatment. Otherwise cTn+ and high-risk sPESI 90-day mortality rate was 43.7 %. No difference was found in terms of secondary endpoints between the patients who received outpatient treatment and those who received inpatient treatment in Group-1 (p = NS). In our study, cancer was present in 16 (51.6 %) of the 31 outpatients. We observed that patients with acute PTE, low-risk sPESI, and negative troponin levels can be safely treated in the outpatient settings. Also the presence of cancer alone does not necessitate hospitalization.

Mycophenolate mofetil versus intravenous cyclophosphamide for induction treatment of proliferative lupus nephritis in a Japanese population: a retrospective study

Objectives: Recent studies have shown that mycophenolate mofetil (MMF) is similar to intravenous cyclophosphamide (IVC) for the treatment of lupus nephritis (LN), but that treatment response may vary according to location and race/ethnicity. Moreover, no studies have been conducted to compare the efficacy of MMF with that of IVC for a Japanese population. We therefore conducted a retrospective study to clarify the efficacy and safety of MMF compared with that of IVC for induction therapy for active LN, classes III and IV, in a Japanese population of 21 patients, 11 of whom received MMF and 10 IVC.Methods: The primary endpoint was expressed as the percentage of responders, who in turn were defined as the patients who met complete or partial response criteria according to the European consensus statement. The secondary endpoints comprised the renal activity component and serological activity.Results: The primary endpoint was achieved in nine (81.8 %) patients receiving MMF and in four (40.0 %) receiving IVC, with no significant difference between the two groups (p = 0.081), while there was also no significant difference between them in terms of secondary endpoints. However, the MMF group suffered significantly fewer hematologic toxic effects than the IVC group.Conclusions: MMF may be used as an alternative to IVC for inducing renal remission of LN in Japanese patients.

Mycophenolate mofetil versus intravenous cyclophosphamide for induction treatment of proliferative lupus nephritis in a Japanese population: a retrospective study

Recent studies have shown that mycophenolate mofetil (MMF) is similar to intravenous cyclophosphamide (IVC) for the treatment of lupus nephritis (LN), but that treatment response may vary according to location and race/ethnicity. Moreover, no studies have been conducted to compare the efficacy of MMF with that of IVC for a Japanese population. We therefore conducted a retrospective study to clarify the efficacy and safety of MMF compared with that of IVC for induction therapy for active LN, classes III and IV, in a Japanese population of 21 patients, 11 of whom received MMF and 10 IVC. The primary endpoint was expressed as the percentage of responders, who in turn were defined as the patients who met complete or partial response criteria according to the European consensus statement. The secondary endpoints comprised the renal activity component and serological activity. The primary endpoint was achieved in nine (81.8%) patients receiving MMF and in four (40.0%) receiving IVC, with no significant difference between the two groups (p=0.081), while there was also no significant difference between them in terms of secondary endpoints. However, the MMF group suffered significantly fewer hematologic toxic effects than the IVC group. MMF may be used as an alternative to IVC for inducing renal remission of LN in Japanese patients.

Addition of Liposomal Daunorubicin (DaunoXome®) to FLAG Significantly Improves Treatment Response in Pediatric Relapsed AML: Final Results From the International Randomised Phase III Study Relapsed AML 2001/01.

Abstract 18 Introduction:Long-term survival in pediatric relapsed AML is only 20-30%. Optimal reinduction therapy is unknown, and there is a concern about cardiotoxicity with repeated anthracycline use at relapse. Preclinical in vitro and animal studies, and limited clinical data suggest that liposomal daunorubicin (DaunoXome®, DNX) is less cardiotoxic. These considerations lead to a phase III study, in the setting of the International BFM Study Group. Materials and methods:FLAG was randomised against FLAG/DNX in the 1st reinduction course. The conventional 5-days FLAG only was recommended as the 2nd course. DNX was dosed at 60 mg/m2/day on days 1, 3 and 5. After induction, allogeneic stem cell transplantation was generally recommended, but time-to-transplant could be bridged by high- or low-intensive consolidation therapy. Primary endpoint of the study was early treatment response, based on bone marrow examination shortly before reinduction course 2, and defined as either good (≤20% leukemic blasts) or poor (>20% leukemic blasts). This endpoint was chosen because of its prognostic value in earlier relapsed AML BFM-trials, and because compliance with an extended protocol guideline was likely to be suboptimal within the context of a highly multinational and multicenter AML Relapse protocol. However, secondary endpoints were defined, including the CR2 rate determined after 2 courses, long-term survival, and toxicity. Patients with AML M3 and those >18 years of age at initial diagnosis were ineligible. The study opened in most countries in 2002/2003. The study closed for accrual on April 1, 2009 when the required 360 fully eligible and evaluable patients had been randomized. Early and late relapsed AML was defined as a relapse within or after 1 year from initial diagnosis, but this only influenced treatment in that early relapsed AML patients were eligible for haploidentical SCT, while late relapsed AML patients were eligible for autologous SCT, if a matched or partly mismatched transplant was not possible. Thirteen groups from 20 countries and >100 centers have enrolled patients, with informed consent and after approval of the study by regulatory authorities. Data are presented according to intention-to-treat, with a median follow-up of 2.7 years for patients at risk. Results:Overall 4-year probability of survival (pOS) was 35% SE 2%, the overall CR2 rate 62%. The good early responders had a 4-year pOS of 45% SE 3% versus 10% SE 3% for poor responders (p<0.0001). Similar differences were seen in the subgroups early relapse (pOS 36% SE 5% vs 5% SE3%) and late relapse (53% SE 4% vs 17% SE7%). For the main endpoint, patients randomized to FLAG/DNX had a 12% higher early good response rate than patients randomized to FLAG, 81% vs 69% (p= 0.009). Within early relapsed AML (52% of all patients), this difference was 17% in favor of DNX (p=0.025), in late relapsed AML it was 8% in favor of DNX (p=0.12). In terms of secondary endpoints, CR2 rate was 10% higher with DNX (68% vs 58%, p=0.047). Overall survival was also higher with DNX, but not significantly: 4-years pOS FLAG 35% SE 4% vs. 40% SE 4% for FLAG/DNX. Toxicity was similar in both groups and was significantly different only for skin eruptions (FLAG 1%, FLAG/DNX 5%, p=0.04). Grade III/IV cardiotoxicity was seen in 5 (3.2%) patients treated with FLAG/DNX (1 grade IV, 4 grade III), and in 2 (1.4%) patients treated with FLAG (1 grade IV, 1 grade III), often coinciding with severe infections and was treatable. Conclusion:adding DNX to FLAG improves treatment response in pediatric relapsed AML, both in terms of BM status after the 1st reinduction course and the CR2 rate after 2 courses. The 5% improved pOS with DNX and FLAG was not statistically significant, but the study was not powered to detect small differences in survival. Furthermore, short-term toxicity of FLAG/DNX was similar to FLAG. Analysis of long-term toxicity will require longer follow-up. In view of these data, standard reinduction chemotherapy for pediatric relapsed AML according to I-BFM-SG protocols should consist of high-dose ara-C plus DNX, but the cumulative dose of anthracyclines should always be taken into account. In addition, pediatric relapsed AML is curable in a subgroup of patients, particularly those with a good early treatment response, irrespective of whether the relapse of AML was early or late. Finally, international collaboration proved to be feasible in the treatment of pediatric relapsed AML, and resulted in the best outcome reported sofar with pOS of 35%. Disclosures:Off Label Use: Liposomal daunorubicin (DaunoXome®) in pediatric relapsed acute myeloid leukemia.

Zoledronic Acid

Zoledronic acid (Zometa), a third-generation amino-bisphosphonate, has been approved in the US, the EU and many other countries worldwide for the prevention of skeletal-related events in patients with bone metastases of malignancy. In several well designed trials, zoledronic acid 4 mg administered as a 15-minute infusion every 3-4 weeks was effective in reducing the occurrence of skeletal complications in patients with bone metastases secondary to multiple myeloma, breast cancer or prostate cancer. Zoledronic acid was as effective as pamidronic acid in reducing the occurrence of skeletal complications in patients with multiple myeloma or breast cancer. In patients with solid tumours other than breast or prostate cancer, zoledronic acid did not show significant clinical benefit over placebo in terms of the primary endpoint; however, some benefit of therapy in terms of secondary endpoints was observed with zoledronic acid relative to placebo. Its efficacy in a broad range of tumours and short infusion time (15 minutes) are an advantage over other available bisphosphonates. Modelled pharmacoeconomic analyses in patients with breast cancer suggested that zoledronic acid therapy is cost effective relative to no therapy with regard to the cost per quality-adjusted life-year (QALY) gained; however, results were mixed when zoledronic acid was compared with other commonly used bisphosphonates. Zoledronic acid is generally well tolerated; the risk of osteonecrosis of the jaw may be minimized by adhering to recommendations regarding dental therapy. Additional efficacy and economic data are required to definitively position zoledronic acid with respect to other bisphosphonates. Nevertheless, available clinical data indicate that zoledronic acid is an effective treatment option for the management of bone metastases of malignancy.

Double-blind placebo-controlled randomised trial of vitamin E and pentoxifylline in patients with chronic arm lymphoedema and fibrosis after surgery and radiotherapy for breast cancer

Background and purposeTreatment-induced arm lymphoedema is a common and distressing complication of curative surgery and radiotherapy for early breast cancer. A number of studies testing alpha-tocopherol (vitamin E) and pentoxifylline suggest evidence of clinical regression of superficial radiation-induced fibrosis but there is only very limited evidence from randomised trials. Arm lymphoedema after lymphatic radiotherapy and surgery has been used in the present study as a clinical system for testing these drugs in a double-blind placebo-controlled randomised phase II trial. Patients and methodsSixty-eight eligible research volunteers with a minimum 20% increase in arm volume at a median 15.5 years (range 2–41) after axillary/supraclavicular radiotherapy (plus axillary surgery in 51/68 (75%) cases) were randomised to active drugs or placebo. All volunteers were given dl-alpha tocopheryl acetate 500mg twice a day orally plus pentoxifylline 400mg twice a day orally, or corresponding placebos, for 6 months. The primary endpoint was volume of the ipsilateral limb measured opto-electronically using a perometer and expressed as a percentage of the contralateral limb volume. ResultsAt 12 months post-randomisation, there was no significant difference between treatment and control groups in terms of arm volume. Absolute change in arm volume at 12 months was 2.5% (95% CI −0.40 to 5.3) in the treatment group compared to 1.2% (95% CI −2.8 to 5.1) in the placebo group. The difference in mean volume change between randomisation groups at 12 months was not statistically significant (P=0.6), −1.3% (95% CI −6.1 to 3.5), nor was there a significant difference in response at 6 months (P=0.7), where mean change in arm volume from baseline in the treatment and placebo groups was −2.3% (95% CI −7.9 to 3.4) and −1.1% (95% CI −3.9 to 1.7), respectively. There were no significant differences between randomised groups in terms of secondary endpoints, including tissue induration (fibrosis) in the irradiated breast or chest wall, pectoral fold or supraclavicular fossa, change in photographic breast/chest wall appearance or patient self-assessment of function and Quality of Life at either 6 or 12 months. ConclusionsThe study fails to demonstrate efficacy of dl-alpha tocopheryl acetate plus pentoxifylline in patients with arm lymphoedema following axillary surgery and lymphatic radiotherapy, nor does it suggest any benefits of these drugs in radiation-induced induration (fibrosis) in the breast, chest wall, pectoral fold, axilla or supraclavicular fossa.