Main Efficacy Endpoint Research Articles

Fifteen-year results of a randomized phase III trial of fenretinide to prevent second breast cancer

Purpose: The synthetic retinoid fenretinide administered for 5 years for prevention of second breast cancer showed no difference after a median of 8 years, but a possible reduction in premenopausal women. We conducted a long-term analysis in a subgroup of women who were regularly followed up in a single center.Patients and methods: We analyzed data after a median follow-up of 14.6 years (IQ range, 12.3–16.3 years) from 1739 women aged 30–70 (872 in the fenretinide arm and 867 in the observation arm), representing 60% of the initial cohort of 2867 women. The main efficacy endpoint was second primary breast cancer (contralateral or ipsilateral).Results: The number of second breast cancers was 168 in the fenretinide arm and 190 in the control arm (hazard ratio = 0.83, 95% CI, 0.67–1.03). There were 83 events in the fenretinide arm and 126 in the observation arm in premenopausal women (HR = 0.62, 95% CI, 0.46–0.83), and 85 and 64 events in postmenopausal women (HR = 1.23, 95% CI, 0.63–2.40). The younger were the women, the greater was the risk reduction associated with fenretinide, which attained 50% in women aged 40 years or younger and disappeared after age 55 (P-age*treatment interaction = 0.023). There was no difference in cancers in other organs, distant metastases or survival.Conclusions: Fenretinide induces a significant risk reduction of second breast cancer in premenopausal women, which is remarkable at younger ages, and persists several years after treatment cessation. Since adverse events are limited, a trial in young women at high-risk is warranted.

Utilisation and Safety of Bemiparin, a??Low-Molecular-Weight Heparin, in??Medical Patients

Venous thromboembolism (VTE) is the cause of approximately 10-12% of all deaths occurring in hospitalised patients. In a previous study, bemiparin suppressed markers of hypercoagulability in acutely ill medical patients with heart failure. To estimate the rate of symptomatic VTE, bleeding events, thrombocytopenia and death in acutely ill medical patients treated with low and high prophylactic doses of bemiparin in standard clinical practice. This was a prospective, open, multicentre, non-randomised cohort study. Acutely ill patients hospitalised in medical departments were included and treated with bemiparin 2500 IU/day or 3500 IU/day, depending on the degree of VTE risk (moderate or high) as assessed by the investigator. The main efficacy and safety endpoints were: symptomatic confirmed VTE (deep vein thrombosis and pulmonary embolism), major bleeding, thrombocytopenia and death. The observation period was 41 days. A total of 297 medical patients hospitalised for several reasons (lung disease: 87 [29.3%], heart disease: 80 [26.9%], neurological disease 25 [8.4%], gastrointestinal disease: 18 [6.1%], rheumatic disorder: 14 [4.7%], haematological disease: 11 [3.7%], renal disease: 8 [2.7%], other: 54 [18.2%]) were included from 13 centres in Spain. The median age of the patients included was 78 years (range 31-100). Overall, 208 patients received bemiparin 2500 IU/day and 89 patients received bemiparin 3500 IU/day. There was one case of symptomatic VTE in 297 patients (0.3%). Four patients (1.3%) experienced a major bleeding event. There were two cases (0.7%) of mild-moderate type I heparin-induced thrombocytopenia (HIT) during the treatment period that did not require treatment discontinuation. There were no cases of severe type II HIT. A total of 22 (7.4%) patients died during the treatment period as a result of factors unrelated to VTE. Bemiparin appears to be effective and safe in the prevention of VTE in acutely ill medical patients.

Efficacy, pharmacokinetic, and safety assessment of adalimumab, a fully human anti-tumor necrosis factor-alpha monoclonal antibody, in adults with rheumatoid arthritis receiving concomitant methotrexate: A pilot study

Background: Because traditional therapies for rheumatoid arthritis (RA) such as methotrexate (MTX) do not produce an adequate response in many patients, newer therapies that block the proinflammatory cytokine tumor necrosis factor-alpha (TNF-alpha) are increasingly being used in combination with MTX. Objective: This study evaluated the efficacy, pharmacokinetics, and safety profile of adalimumab, a fully human anti-TNF alpha monoclonal antibody, when added to continuing MTX therapy. Methods: This Phase I, randomized, dose-titration study consisted of a 4-week, double-blind, placebo-controlled treatment phase and a 26-month, open-label continuation phase. Patients with RA who had been taking stable doses of MTX (mean dose, 17 mg/wk) for ≥3 months before enrollment with an inadequate response were randomly assigned to receive 2 single doses of either adalimumab 0.25, 0.5, 1, 3, or 5 mg/kg IV or placebo in the double-blind phase. In the open-label phase, patients received treatment with 1 of the doses of adalimumab every other week or monthly for 18 months; patients were then switched to adalimumab 40 mg IV or SC every other week or monthly. The main efficacy end point was 20% improvement in American College of Rheumatology response criteria (ACR20). Other efficacy end points included 50% (ACR50) and 70% improvements in ACR response criteria. Pharmacokinetic parameters were analyzed for adalimumab and MTX during both phases of the study. Serum adalimumab concentrations were analyzed using a validated enzyme-linked immunosorbent assay relying on the double-antigen principle. Peak and trough concentrations were determined from observed concentration-time data, and a modeling approach was used to estimate total serum clearance, mean apparent terminal half-life, apparent volume of distribution at steady state, and area under the concentration-time curve. Results: Sixty patients entered the double-blind phase, 45 receiving adalimumab and 15 receiving placebo; 1 placebo recipient chose not to continue into the open-label phase. Overall, the study population included 47 (78.3%) women and 13 (21.7%) men. The mean age was 52.9 years (range, 24–73 years), and the mean body weight was 69.7 kg (range, 43–98 kg). ACR20 and ACR50 responses were achieved on at least 1 assessment during the 4-week double-blind phase by a respective 29 (64.4%) and 11 (24.4%) of 45 patients receiving active treatment and by 4 (26.7%) and none of the 15 patients receiving placebo. Responses to adalimumab were rapid, with 10 (22.2%) of 45 patients achieving an ACR20 response within 24 hours of dosing. Of 29 adalimumab recipients who had an ACR20 response, 18 (62.1%) had a duration of response (time from first occurrence of a response to first occurrence of a nonresponse) of 1 to 2 weeks, and 11 (37.9%) had a duration of response of 3 to 13 weeks. The pharmacokinetic properties of adalimumab appeared to be linear. The mean apparent terminal half-life after a single intravenous dose of adalimumab ranged from 15 to 19 days in the 5 dose groups. Repeated administration of adalimumab had no statistically significant effect on the pharmacokinetics of MTX, indicating that dose adjustment of MTX is not necessary. Adalimumab was well tolerated, and there were no dose-related adverse events. Conclusions: Among patients with active RA who had not had an adequate response to MTX, addition of adalimumab to MTX achieved statistically significant, long-term improvement compared with placebo plus MTX ( P ≤ 0.05), as indicated by ACR responses at 26 months. The combination was well tolerated. Adalimumab exhibited linear pharmacokinetics. In this selected patient population, adalimumab's long half-life of 15 to 19 days supports every-other-week dosing. Coadministration of adalimumab did not alter serum levels of MTX.

Effectiveness and tolerability of ibuprofen‐arginine versus paracetamol in children with fever of likely infectious origin

The aim of this multicentre, double‐blind, randomized study was to assess the paediatric antipyretic efficacy of a new ibuprofen formulation containing L‐arginine for gastric protection, compared with the efficacy of paracetamol. For this purpose 100 patients were given ibuprofen‐arginine (1 drop/kg: 6.67mg/kg) and 99 paracetamol (4 drops/kg: 10.65 mg/kg). The main efficacy endpoint was the mean change in tympanic temperature 4 h after drug intake. Twelve patients were excluded because of early vomiting or spitting out the medication. The resulting efficacy analysis population included a total of 88 patients treated with ibuprofen‐arginine and 87 with paracetamol. Mean change in tympanic temperature (°C) showed no difference between groups (p= 0.527) but more patients in the ibuprofen‐arginine group attained a temperature reduction greater than 2°C (p= 0.043). A total of 107 patients required antipyretic rescue medication, with a smaller proportion in the ibuprofen‐arginine group. Although this was not statistically significant, a trend towards improved activity was observed (p= 0.100). Overall efficacy was judged from the recovery or improvement in 68.8% of patients in the ibuprofen‐arginine group compared with 65.5% in the paracetamol group. Nineteen patients reported adverse events, with vomiting being the most common complaint, but no differences were detected between treatments. Conclusion: Based on the present results, ibuprofen‐arginine oral drops have shown to be a safe, well‐tolerated and potent paediatric antipyretic agent. Hence, ibuprofen‐arginine should be considered as an adequate choice for the control of paediatric fever of likely infectious aetiology.

Gemcitabine plus epirubicin in advanced pancreatic cancer: A phase II multicenter trial

The aim of this phase II multicenter trial was to evaluate the activity of a novel combination of gemcitabine (GEM) and epirubicin (EPI) in advanced pancreatic cancer patients. Clinical benefit and response rate were the main efficacy end-points. From December 1997 to October 1999, 30 consecutive patients with measurable advanced pancreatic cancer were enrolled. Gemcitabine was administered intravenously in 30 min at a dose of 800 mg/m2 on days 1, 8, 15 followed by i.v. injection of epirubicin 25 mg/m(2); treatment was repeated every 28 days. With regard to clinical benefit response, 8/21 patients (38%) experienced significant palliation of tumor-related symptoms; the median symptom control time was 25 weeks. No complete responses were recorded while 6 patients achieved a partial remission, for an overall response rate of 20%; 10 patients (30%) had a stable disease and 14 (46%) had progressive disease. The median time to progression was 14 weeks. Median survival was 26 weeks, with 6 patients (20%) having long-term survival at 46 weeks. In general, chemotherapy was well tolerated; 9 patients (30%) suffered from WHO grade 3-4 haematological toxicity and 5 patients (16.6%) suffered from grade 3 non-haematological toxicity. In conclusion, the GEM plus EPI regimen represent a feasible approach for improvement of clinical benefit in advanced pancreatic cancer patients, but confirmatory investigations are required.

A Baseline Covariate Adjusted Chi-Square Test for Binary and Categorical Data

We propose a test of comparison of treatment groups adjusted based on information brought by a baseline covariate in a randomized clinical trial for which the main efficacy endpoint is a binary or a categorical criterion. This test is linked to the statistical information notions of Kullback-Leibler information and I-projection and leads to a lest statistic that must be compared to the chi-square distribution with the same degrees of freedom as the Pearson chi-square test. With some simulations, the nonasymptotic properties of this test have been investigated: it is shown that in some cases the power of this adjusted test is superior to the Pearson chi-square test whereas the type I error is less sensitive to the large baseline empirical differences of the prognostic covariate.

A Multicenter Randomized Double-blind Study of Enoxaparin Compared with Unfractionated Heparin in the Prevention of Venous Thromboembolic Disease in Elderly In-patients Bedridden for an Acute Medical Illness

A multicenter, randomized double-blind study compared in two parallel groups the efficacy and safety of a low molecular weight heparin (LMWH) enoxaparin 20 mg once daily, with unfractionated heparin (UFH) 5000 IU twice daily, administered subcutaneously for 10 days, in the prevention of venous thrombosis disease in 442 hospitalized elderly patients bedridden for an acute medical illness. The main efficacy endpoint was defined as the occurrence of venous thrombosis, diagnosed by a daily fibrinogen uptake test, and/or documented clinical pulmonary embolism. Intention-to-treat analysis of efficacy showed that the incidence of venous thromboembolic events was low: 4.8% (10/207) in the LMWH group (9 episodes of isotopic venous thrombosis and one of scintigraphic pulmonary embolism), and 4.6% (10/216) in the UFH group (10 episodes of isotopic venous thrombosis). The two treatments were equivalent, where equivalence was defined as a maximum difference of 7% between the two groups (p = 0.0005). There were no significant differences in terms of safety between the 216 patients in the LMWH group and the 223 patients in the UFH group who received at least one injection of the randomized treatment. During the study period, 15 patients (3.4%) died (7 in the LMWH group and 8 in the UFH group): 2 sudden deaths, one in each group including one case in which pulmonary embolism could not be excluded since no autopsy was performed, and 13 others deaths unrelated to the study treatments. Six patients (1.4%) presented a bleeding complication: 2 (0.9%) in the enoxaparin group (one major and one minor hemorrhage), and 4 (1.8%) in the UFH group (2 major and 2 minor hemorrhages). These results indicate that subcutaneous enoxaparin 20 mg once daily for 10 days is as effective and well tolerated as subcutaneous UFH 5000 IU twice daily in the prevention of venous thromboembolic disease in bedridden elderly in-patients presenting an acute medical illness.