Main Efficacy Endpoint Research Articles

Effect of low-dose amitriptyline on globus pharyngeus and its side effects

To compare the efficacy and side effects of low-dose amitriptyline (AMT) with proton pump inhibitor treatment in patients with globus pharyngeus. Thirty-four patients who fulfilled the Rome III criteria for functional esophageal disorders were included in this study. Patients were randomly assigned to receive either 25 mg AMT before bedtime (AMT group) or 40 mg Pantoprazole once daily for 4 wk (conventional group). The main efficacy endpoint was assessed using the Glasgow Edinburgh Throat Scale (GETS). The secondary efficacy endpoints included the Medical Outcomes Study 36-item short form health survey [social functioning (SF)-36] and the Pittsburgh Sleep Quality Index. Treatment response was defined as a > 50% reduction in GETS scores. All patients entering this study recorded side effects at days 1, 8, 15, 22 and 29 using a visual analogue scale. Thirty patients completed the study. After 4 wk of treatment, the AMT group had a greater response than the conventional group (75% vs 35.7%, P = 0.004). At day 3, the AMT group showed significantly more improvement than the Conventional group in GETS score (3.69 ± 1.14 vs 5.64 ± 1.28, P = 0.000). After 4 wk of treatment, the AMT group showed significantly greater improvement in GETS score and sleep quality than the Conventional group (1.25 ± 1.84 vs 3.79 ± 2.33, 4.19 ± 2.07 vs 8.5 ± 4.97; P < 0.01 for both). Additionally, the AMT group was more likely than the Conventional group to experience improvement in the SF-36, including general health, vitality, social functioning and mental health (P = 0.044, 0.024, 0.049 and 0.005). Dry mouth, sleepiness, dizziness and constipation were the most common side effects. Low-dose AMT is well tolerated and can significantly improve patient symptoms, sleep and quality of life. Thus, low-dose AMT may be an effective treatment for globus pharyngeus.

Effects of Fibrinogen Concentrate as First-line Therapy during Major Aortic Replacement Surgery

Fibrinogen is suggested to play an important role in managing major bleeding. However, clinical evidence regarding the effect of fibrinogen concentrate (derived from human plasma) on transfusion is limited. The authors assessed whether fibrinogen concentrate can reduce blood transfusion when given as intraoperative, targeted, first-line hemostatic therapy in bleeding patients undergoing aortic replacement surgery. In this single-center, prospective, placebo-controlled, double-blind study, patients aged 18 yr or older undergoing elective thoracic or thoracoabdominal aortic replacement surgery involving cardiopulmonary bypass were randomized to fibrinogen concentrate or placebo, administered intraoperatively. Study medication was given if patients had clinically relevant coagulopathic bleeding immediately after removal from cardiopulmonary bypass and completion of surgical hemostasis. Dosing was individualized using the fibrin-based thromboelastometry test. If bleeding continued, a standardized transfusion protocol was followed. Twenty-nine patients in the fibrinogen concentrate group and 32 patients in the placebo group were eligible for the efficacy analysis. During the first 24 h after the administration of study medication, patients in the fibrinogen concentrate group received fewer allogeneic blood components than did patients in the placebo group (median, 2 vs. 13 U; P < 0.001; primary endpoint). Total avoidance of transfusion was achieved in 13 (45%) of 29 patients in the fibrinogen concentrate group, whereas 32 (100%) of 32 patients in the placebo group received transfusion (P < 0.001). There was no observed safety concern with using fibrinogen concentrate during aortic surgery. Hemostatic therapy with fibrinogen concentrate in patients undergoing aortic surgery significantly reduced the transfusion of allogeneic blood products. Larger multicenter studies are necessary to confirm the role of fibrinogen concentrate in the management of perioperative bleeding in patients with life-threatening coagulopathy.

Primary and secondary prevention with new oral anticoagulant drugs for stroke prevention in atrial fibrillation: indirect comparison analysis

Objective To do an indirect comparison analysis of apixaban against dabigatran etexilate (2 doses) and rivaroxaban (1 dose), as well as of rivaroxaban against dabigatranetexilate (2 doses), for their relative...

Critères d’évaluation des thérapeutiques dans les cancers de la prostate avancés

In castrate-refractory prostate cancers, main efficacy endpoints are progression free survival for phase-II trials and overall survival for phase-III trials. However, various progression criteria have been used, and overall survival may become more difficult to impact due to the recent approval of more effective drugs. PSA is useful in clinical practice, provided it is interpreted with caution, but cannot be used as a surrogate endpoint in clinical trials. Finally, circulating tumor cells represent a promising area of development.

Dabigatran, Rivaroxaban and Apixaban versus Enoxaparin for thomboprophylaxis after total knee or hip arthroplasty: Pool-analysis of phase III randomized clinical trials

ObjectivesTo compare the main efficacy and safety endpoints of the pivotal randomised clinical trials (RCTs) on venous thromboembolism (VTE) prevention after total hip (THR) or knee (TKR) replacement with the new oral anticoagulants (NAs) versus enoxaparin. MethodsA pool-analysis of 10 RCTs that included 32.144 randomised patients was performed. Efficacy outcomes were total VTE and all-cause mortality, major VTE, and proximal DVT. Safety outcomes were major bleeding, and clinically relevant (major or non-major) bleeding. ResultsOverall, a significant effect favouring NAs was found for the primary efficacy outcome (RR 0.71; 95%CI 0.56-0.90), major VTE (RR 0.59; 95%CI 0.41-0.84), and proximal DVT (RR 0.51; 95%CI 0.35-0.76). Compared to enoxaparin 40mg QD, rivaroxaban showed superiority (RR 0.50; 95%CI 0.34-0.73), followed by apixaban (RR 0.63; 95%CI 0.36-1.01) and dabigatran (RR 1.02; 95%CI 0.86-1.20). There was significant heterogeneity among trials and subgroups analysed for these efficacy outcomes. Major bleeding (RR 1.04; 95% CI 0.74-1.46) and clinically relevant bleeding (RR 1.03; 95%CI 0.88-1.21) was similar with NAs or enoxaparin. Rivaroxaban showed a trend toward more major bleeding episodes than enoxaparin (RR 1.88; 95%CI 0.92-3.82) and apixaban showed the lowest clinically relevant bleeding risk (RR 0.81; 95%CI 0.64-1.01). ConclusionsOverall, NAs showed more efficacy and same safety when compared to the recommended dose of enoxaparin after THR and TKR. There are little differences in efficacy and bleeding risk among NAs and the type of prophylaxis that should be analysed further.

Low dose estriol pessaries for the treatment of vaginal atrophy: A double-blind placebo-controlled trial investigating the efficacy of pessaries containing 0.2 mg and 0.03 mg estriol

ObjectiveThe aim of the study was to confirm the superior efficacy of estriol containing pessaries compared to placebo in the treatment of vaginal atrophy. Study designIn a prospective, multicenter, randomized, placebo-controlled, double-blind study, 436 postmenopausal women with vaginal atrophy (vaginal maturation index, VMI<40%; vaginal pH>5; most bothersome symptom, MBS≥65 on visual analogue scale, VAS) were treated with pessaries containing either 0.2mg estriol (N=142) or 0.03mg estriol (N=147) or with a matching placebo (N=147) for 12 weeks. Main outcome measuresPrimary efficacy endpoints included increase in VMI, decrease of the vaginal pH value and decrease in intensity of MBS after 12 weeks of treatment. ResultsThe increase in VMI was significantly greater under 0.2mg estriol and 0.03mg estriol (46.3±17.0 and 38.4±19.4, respectively) compared to placebo (23.9±21.5; p values<0.001), vaginal pH decreased significantly more (−1.6±0.8 and −1.4±0.9, respectively) compared to placebo (−0.6±0.8; p values<0.001) and MBS intensity (VAS) declined significantly more (−52.2±23.7 and −47.1±23.4, respectively) compared to placebo (−31.8±26.3; p values<0.001). Adverse events were rare and occurred at similar rates in all three groups. ConclusionsSuperiority of estriol containing pessaries over placebo was shown in the local treatment of vaginal atrophy. Even a very low dose of 0.03mg estriol proved sufficient for local treatment of vaginal atrophy with excellent tolerability.

Study on the use of omega-3 fatty acids as a therapeutic supplement in treatment of psoriasis

Previous studies have suggested a benefit for patients with plaque psoriasis when omega-3 fatty acids are added to topical treatment. This study evaluated the efficacy of a nutritional complement rich in omega-3 fatty acids in patients with mild or moderate plaque psoriasis. Thirty patients were recruited, 15 of whom were given topical treatment with tacalcitol, forming the control group. The remaining 15 patients were given topical tacalcitol and 2 capsules of Oravex® daily. Three visits, the baseline, intermediate (week 4), and final (week 8), were held over an 8-week period. The main efficacy endpoints were the Psoriasis Area and Severity Index (PASI), Nail Psoriasis Severity Index (NAPSI) and Dermatological Life Quality Index (DLQI). A clear and significant improvement was observed in all the efficacy endpoints in both groups between the baseline visit and the end visit. This improvement was significantly greater in the group treated additionally with Oravex® than in the control group. Supplementary treatment with omega-3 fatty acids complements topical treatment in psoriasis, and makes a significant contribution to reducing PASI and NAPSI and improving DLQI; and to reducing scalp lesion and pruritus, erythema, scaling, and infiltration of the treated areas.

Longterm Therapeutic Response to Milnacipran Treatment for Fibromyalgia. A European 1-Year Extension Study Following a 3-Month Study

This double-blind, 1-year extension study investigated the longterm efficacy and safety of milnacipran 100, 150, and 200 mg/day in the treatment of fibromyalgia (FM) in completers of a 3-month European double-blind lead-in study of milnacipran 200 mg/day versus placebo. A total of 468 patients with FM successfully completing the lead-in study were either blindly maintained on milnacipran 200 mg/day (MLN200:MLN200, n = 198) or (if previously receiving placebo) rerandomized to milnacipran 100 mg/day (PBO:MLN100, n = 91), 150 mg/day (PBO:MLN150, n = 92), or 200 mg/day (PBO:MLN200, n = 87) for an additional 12 months (including a 4-week dose escalation). The main efficacy endpoint was a 2-measure composite responder rate (relative to lead-in study baseline) incorporating the weekly-recall pain score recorded on a visual analog scale and the Patient Global Impression of Change score. A panel of other assessments including the Fibromyalgia Impact Questionnaire explored the multidimensional aspects of FM. Descriptive analyses using the last observation carried forward approach were performed. At the 1-year endpoint, the proportion of composite responders (relative to the lead-in study baseline) ranged from 27.5% (PBO:MLN100) to 35.9% (MLN200:MLN200), and had increased from the extension study baseline by 15.2% (PBO:MLN150) to 20.7% (PBO:MLN200 and MLN200:MLN200). At endpoint, an improvement from both baselines was shown in all groups on pain, fatigue, sleep, and quality of life measures. Up to 1 year, all doses of milnacipran were safe and well tolerated. The most common drug-related adverse events were hyperhidrosis and nausea. Over 1 year, milnacipran 100, 150, and 200 mg/day exhibited sustained and safe therapeutic effects on predominant symptoms of FM. Registered as trial no. NCT00757731.

Twice-Daily, Preservative-Free Ketorolac 0.45% for Treatment of Inflammation and Pain After Cataract Surgery

To evaluate the efficacy and safety of twice-daily, preservative-free ketorolac 0.45% (Acuvail; Allergan, Inc, Irvine, California, USA) administration for treatment of inflammation and pain after cataract surgery. Prospective, randomized trial. Two multicenter, double-masked studies randomized 511 cataract surgery patients (2:1) to receive twice-daily ketorolac 0.45% or vehicle in the operative eye for 16 days, beginning 1 day before surgery. The primary efficacy end point was the percentage of patients with a summed ocular inflammation score of 0 for anterior chamber cell and flare on postoperative day 14. The main secondary efficacy end point was the percentage of patients with no pain on postoperative day 1. On day 14, 52.5% of ketorolac patients and 26.5% of vehicle patients had an summed ocular inflammation score of 0 (P < .001). On day 1, 72.4% of ketorolac patients and 39.7% of vehicle patients had a pain score of 0 (P < .001). Median time to pain resolution was 1 day in the ketorolac group and 2 days in the vehicle group (P < .001). The percentage of ketorolac and vehicle patients who had a +3-line or more improvement in best-corrected visual acuity from baseline was 60.5% versus 44.0% on day 14 (P = .002). Overall, adverse events were more prevalent in the vehicle group than in the ketorolac group (48.5% vs 35.2%; P = .004). Burning or stinging (per a composite Medical Dictionary for Regulatory Activities) was reported by 1.5% of ketorolac patients and 0.6% of vehicle patients. Twice-daily ketorolac 0.45% was well tolerated and effectively treated inflammation and pain following cataract surgery.

Association of KRAS p.G13D Mutation With Outcome in Patients With Chemotherapy-Refractory Metastatic Colorectal Cancer Treated With Cetuximab

Patients with metastatic colorectal cancer who have KRAS codon 12- or KRAS codon 13-mutated tumors are presently excluded from treatment with the anti-epidermal growth factor receptor monoclonal antibody cetuximab. To test the hypothesis that KRAS codon 13 mutations are associated with a better outcome after treatment with cetuximab than observed with other KRAS mutations. We studied the association between KRAS mutation status (p.G13D vs other KRAS mutations) and response and survival in a pooled data set of 579 patients with chemotherapy-refractory colorectal cancer treated with cetuximab between 2001 and 2008. Patients were included in the CO.17, BOND, MABEL, EMR202600, EVEREST, BABEL, or SALVAGE clinical trials or received off-study treatment. Univariate and multivariate analyses, adjusting for possible prognostic factors and data set, were performed. The effect of the different mutations was studied in vitro by constructing isogenic cell lines with wild-type KRAS, p.G12V, or p.G13D mutant alleles and treating them with cetuximab. The main efficacy end point was overall survival. Secondary efficacy end points were response rate and progression-free survival. In comparison with patients with other KRAS-mutated tumors, patients with p.G13D-mutated tumors (n = 32) treated with cetuximab had longer overall survival (median, 7.6 [95% confidence interval {CI}, 5.7-20.5] months vs 5.7 [95% CI, 4.9-6.8] months; adjusted hazard ratio [HR], 0.50; 95% CI, 0.31-0.81; P = .005) and longer progression-free survival (median, 4.0 [95% CI, 1.9-6.2] months vs 1.9 [95% CI, 1.8-2.8] months; adjusted HR, 0.51; 95% CI, 0.32-0.81; P = .004). There was a significant interaction between KRAS mutation status (p.G13D vs other KRAS mutations) and overall survival benefit with cetuximab treatment (adjusted HR, 0.30; 95% CI, 0.14-0.67; P = .003). In vitro and mouse model analysis showed that although p.G12V-mutated colorectal cells were insensitive to cetuximab, p.G13D-mutated cells were sensitive, as were KRAS wild-type cells. In this analysis, use of cetuximab was associated with longer overall and progression-free survival among patients with chemotherapy-refractory colorectal cancer with p.G13D-mutated tumors than with other KRAS-mutated tumors. Evaluation of cetuximab therapy in these tumors in prospective randomized trials may be warranted.

Efficacy and Tolerability of Preservative-Free Eye Drops Containing a Fixed Combination of Dorzolamide and Timolol in Glaucoma Patients

To evaluate the efficacy and tolerability of preservative-free eye drops (dorzolamide/timolol) in routine management of preservative-sensitive glaucoma patients. Data from 2,298 glaucoma patients requiring intraocular pressure (IOP) reduction and suffering from intolerance to benzalkonium chloride or active agents of previously used eye drops were valid for baseline and safety analysis in this prospective, open, noncomparative, multicenter, noninterventional study. Patients were treated with preservative-free dorzolamide/timolol eye drops for 12 weeks. Main efficacy endpoint was IOP reduction after 12 weeks of treatment. Two thousand forty-nine patients were considered for efficacy analysis. Tolerability was assessed by evaluating adverse drug reactions. Mean baseline IOP was 20.8 mmHg. Baseline IOP was reduced to 16.7 mmHg after 12 weeks of treatment corresponding to a mean absolute (percent) change of -4.1 mmHg (-17.3%). The proportion of patients with IOP ≤21 mmHg increased from 59.9% at baseline to 94.6% after 12 weeks. The most frequently reported ocular adverse drug reactions were burning eyes (2.4%) and hyperemia (0.9%). Local tolerability improved in 79.3% of patients compared to their previous glaucoma therapy. This observational study confirms the IOP lowering effect of preservative-free eye drops containing the fixed combination of dorzolamide/timolol in a large patient's population. The drug was well tolerated and improved the local tolerability in the vast majority of patients.

A Randomized Study to Demonstrate Noninferiority of Once-Daily OROS® Hydromorphone with Twice-Daily Sustained-Release Oxycodone for Moderate to Severe Chronic Noncancer Pain

This was a randomized, open-label, comparative, parallel group study designed to demonstrate the noninferiority of once-daily OROS(®) hydromorphone compared with twice-daily sustained-release (SR) oxycodone in subjects with chronic noncancer pain severe enough to require continuous opioid therapy. The core phase (24 weeks) consisted of titration and maintenance periods. This was followed by an optional extension phase (28 weeks), which collected data used to assess long-term safety and efficacy outcomes. Five hundred four subjects were randomized between the 2 treatment groups. The primary efficacy analysis showed that OROS hydromorphone was noninferior to SR oxycodone (P = 0.011) as measured by change in Brief Pain Inventory (BPI) pain severity subscore "pain right now." The treatment difference with respect to change in BPI pain severity subscore "pain right now" was 0.29 (95% confidence interval: -0.27 to 0.84). The equianalgesic doses were 16 mg OROS hydromorphone and 40 mg SR oxycodone (median values). Secondary outcomes included other BPI scale items, the Medical Outcomes Study (MOS) Sleep Indices, and quality of life measured by the Short Form 36 (SF-36) questionnaire. Both treatment groups showed improvements in the main secondary efficacy endpoints. No statistically significant differences were shown between the treatment groups, except for the scores for somnolence (MOS sleep subscale) and physical functioning (SF-36), which both had a statistically significant difference between treatments groups in favor of OROS hydromorphone. Both study medications had equivalent and acceptable safety profiles. The results of this open-label study showed that once-daily OROS hydromorphone is a safe and well-tolerated treatment for chronic pain and as efficacious as twice-daily SR oxycodone.

Siltuximab, a Novel Anti–Interleukin-6 Monoclonal Antibody, for Castleman's Disease

Interleukin-6 (IL-6) has emerged as a key factor in the pathogenesis of the atypical lymphoproliferative disorder Castleman's disease (CD). Siltuximab is a new anti-IL-6, chimeric monoclonal antibody with potential therapeutic benefit in patients with CD. We report interim results from an open-label, dose-finding, seven-cohort, phase I study in which patients with symptomatic, multicentric or unresectable, unicentric CD received siltuximab at 1-, 2-, or 3-week intervals. The main efficacy end point of clinical benefit response (CBR) was defined as a composite of clinical and laboratory measures relevant to the management of CD. In addition, radiologic response was independently assessed by using modified Cheson criteria. Eighteen (78%) of 23 patients (95% CI, 56% to 93%) achieved CBR, and 12 patients (52%) demonstrated objective tumor response. All 11 patients (95% CI, 72% to 100%) treated with the highest dose of 12 mg/kg achieved CBR, and eight patients (73%) achieved objective tumor response. Overall objective-response duration ranged from 44 to > or = 889 days, and one patient had complete response for > or = 318 days. Hemoglobin increased markedly in 19 patients (median increase, 2.1 g/dL; range, 0.2 to 4.7 g/dL) in the absence of transfusion or erythropoiesis-stimulating agents. No dose-limiting toxicity was reported, and only three patients had grade 3 or higher adverse events after a median exposure of 331 days (range, 1 to 1,148 days). These interim results strongly suggest that siltuximab is an effective treatment with favorable safety for the management of CD. An additional study is planned to fully evaluate safety and efficacy at the recommended dose of 12 mg/kg every 3 weeks.

Early Cervical Cancer Managed by Laparoscopy and Conventional Surgery

The goal of this retrospective analysis was to compare the results of treatment in patients with early cervical cancer managed by laparoscopy with those for patients observed after laparotomy. The retrospective analysis was carried out with 22 patients operated on with total laparoscopic hysterectomy and 58 patients treated by abdominal hysterectomy. Patients with clinical tumor stage IA, IB1, or IIA were eligible for surgery. The main efficacy end point was disease-free survival evaluated by the Kaplan-Meier method. The survival curves were compared using log-rank tests. In addition, length of hospitalization, duration of surgery, and complication rate were compared. P < 0.05 was set as statistically significant. Predicted 3-year disease-free survival rates in the "open surgery" and "laparoscopy" groups were 0.86 (standard deviation [SD], 0.049) and 0.82 (SD, 0.098), respectively (P = 0.53). Recurrence rate was 13.6% after laparoscopy and 12% in open surgery. In 2 patients, intraperitoneal spread occurred after laparoscopy. The operation time was longer and hospitalization shorter after laparoscopy. The 3-year disease-free survival was similar in both groups. Total laparoscopic radical hysterectomy may be an option in early cervical cancer; however, the intraperitoneal spread in 2 patients compels a search for possible risk factors in patients managed by laparoscopy.

Rivaroxaban versus placebo in patients with acute coronary syndromes (ATLAS ACS-TIMI 46): a randomised, double-blind, phase II trial

Rivaroxaban is an oral direct factor Xa inhibitor that has been effective in prevention of venous thromboembolism in patients undergoing elective orthopaedic surgery. However, its use after acute coronary syndromes has not been investigated. In this setting, we assessed the safety and efficacy of rivaroxaban and aimed to select the most favourable dose and dosing regimen. In this double-blind, dose-escalation, phase II study, undertaken at 297 sites in 27 countries, 3491 patients stabilised after an acute coronary syndrome were stratified on the basis of investigator decision to use aspirin only (stratum 1, n=761) or aspirin plus a thienopyridine (stratum 2, n=2730). Participants were randomised within each strata and dose tier with a block randomisation method at 1:1:1 to receive either placebo or rivaroxaban (at doses 5-20 mg) given once daily or the same total daily dose given twice daily. The primary safety endpoint was clinically significant bleeding (TIMI major, TIMI minor, or requiring medical attention); the primary efficacy endpoint was death, myocardial infarction, stroke, or severe recurrent ischaemia requiring revascularisation during 6 months. Safety analyses included all participants who received at least one dose of study drug; efficacy analyses were by intention to treat. This study is registered with ClinicalTrials.gov, number NCT00402597. Three patients in stratum 1 and 26 in stratum 2 never received the study drug. The risk of clinically significant bleeding with rivaroxaban versus placebo increased in a dose-dependent manner (hazard ratios [HRs] 2.21 [95% CI 1.25-3.91] for 5 mg, 3.35 [2.31-4.87] for 10 mg, 3.60 [2.32-5.58] for 15 mg, and 5.06 [3.45-7.42] for 20 mg doses; p<0.0001). Rates of the primary efficacy endpoint were 5.6% (126/2331) for rivaroxaban versus 7.0% (79/1160) for placebo (HR 0.79 [0.60-1.05], p=0.10). Rivaroxaban reduced the main secondary efficacy endpoint of death, myocardial infarction, or stroke compared with placebo (87/2331 [3.9%] vs 62/1160 [5.5%]; HR 0.69, [95% CI 0.50-0.96], p=0.0270). The most common adverse event in both groups was chest pain (248/2309 [10.7%] vs 118/1153 [10.2%]). The use of an oral factor Xa inhibitor in patients stabilised after an acute coronary syndrome increases bleeding in a dose-dependent manner and might reduce major ischaemic outcomes. On the basis of these observations, a phase III study of low-dose rivaroxaban as adjunctive therapy in these patients is underway. Johnson & Johnson Pharmaceutical Research & Development and Bayer Healthcare AG.

Once-Daily Oral Rivaroxaban Compared with Subcutaneous Enoxaparin Every 12 Hours for Thromboprophylaxis after Total Knee Replacement: RECORD4

Rivaroxaban is an oral, direct Factor Xa inhibitor that has been evaluated in the RECORD phase III clinical trial program for the prevention of venous thromboembolism (VTE) in major orthopaedic surgery. RECORD3 (Lassen M, et al. N Engl J Med 2008; 358:2776–2786) showed that oral rivaroxaban 10 mg once daily (od) given post-operatively significantly reduced VTE after total knee replacement (TKR), compared with subcutaneous (s.c.) enoxaparin 40 mg od initiated pre-operatively, with similar rates of bleeding. RECORD4 was designed to determine the efficacy and safety of rivaroxaban compared with enoxaparin 30 mg administered twice daily after TKR. Patients (N=3,148) were randomized to receive either oral rivaroxaban 10 mg od (initiated 6–8 hours after surgery) or s.c. enoxaparin 30 mg every 12 hours (initiated 12 to 24 hours after surgery) for 10 to 14 days. Patients underwent mandatory, bilateral venography between day 11 and day 15. The primary efficacy endpoint was the composite of any deep vein thrombosis (DVT), non-fatal pulmonary embolism (PE), and all-cause mortality up to day 17. The primary efficacy analysis was a test for non-inferiority in the per-protocol population (n=1,702), followed by a test for superiority in the modified intention-to-treat population (n=1,924) (if non-inferiority was established in the per-protocol population). The main secondary efficacy endpoint was major VTE: the composite of proximal DVT, non-fatal PE, and VTE-related death. Treatment-emergent major bleeding observed no later than two days after the last intake of study was the main safety endpoint. The results are shown in the table. Rivaroxaban significantly reduced the incidence of the primary efficacy outcome compared with enoxaparin (6.9% vs 10.1%, respectively; p=0.012; relative risk reduction 31%). Rivaroxaban was non-inferior to enoxaparin for the prevention of major VTE in the per-protocol population (p<0.001). The observed incidences of major VTE and symptomatic VTE in those receiving rivaroxaban or enoxaparin were 1.2% vs 2.0% (p=0.124), and 0.7% vs 1.2% (p=0.187), respectively, and the rates of major bleeding were 0.7% vs 0.3% (p=0.110) respectively, and major and clinically relevant non-major bleeding 3.0% vs 2.3% (p=0.179) in the rivaroxaban and enoxaparin treated groups, respectively. The data demonstrate that rivaroxaban has superior efficacy to enoxaparin 30 mg administered every 12 hours for the prevention of VTE after TKR, without significantly increasing the risk of bleeding.EndpointRivaroxaban10 mg od % (n/N)Enoxaparin30 mg q12h % (n/N)p-value for differencedDVT, non-fatal PE, and all-cause mortalitya6.9% (67/965)10.1% (97/959)0.012Major VTEb1.2% (13/1,122)2.0% (22/1,112)0.124Symptomatic VTEc0.7% (11/1,526)1.2% (18/1,508)0.187Major bleedingc0.7% (10/1,526)0.3% (4/1,508)0.110Any non-major bleedingc10.2% (155/1,526)9.2% (138/1,508)–Major and clinically relevant non-major bleedingc3.0% (46/1526)2.3% (34/1,508)0.179aModified intention-to-treat populationbModified intention-to-treat population valid for major VTE analysiscSafety populationdCalculated for the absolute risk difference

Imiquimod 5% cream for treatment of HIV-negative Kaposi's sarcoma skin lesions: A phase I to II, open-label trial in 17 patients

Kaposi's sarcoma (KS), a virus-associated neoplasm, can be treated locally or systemically with interferon alfa. Therefore, imiquimod, an immune response modifier able to induce interferon-alpha secretion in situ, could prove a good local treatment for KS skin lesions. We sought to determine the efficacy and safety of imiquimod 5% cream for the topical treatment of classic or endemic KS skin lesions in patients who are HIV negative. We conducted a prospective, open-label, single center, phase II clinical trial. Imiquimod cream was applied under occlusion 3 times a week for 24 weeks. The main efficacy end points were the safety of topical imiquimod and the overall clinical response in patients evaluated on the basis of modified AIDS Clinical Trials Group criteria at 36 weeks. The statistical analysis was based on the intent-to-treat data set. Seventeen patients were enrolled. Eight (47%) presented objective overall clinical response (2 complete and 6 partial responses). Tumor progression was noted in 6 patients. The most frequent side effects were local itching and erythema, seen in 9 patients (53%). This was not a randomized placebo-controlled study and was restricted to a small number of patients. Topical imiquimod 5% cream had antitumor activity in about half the patients with classic and endemic KS and was generally well tolerated.

Oral Rivaroxaban Compared with Subcutaneous Enoxaparin for Extended Thromboprophylaxis after Total Hip Arthroplasty: The RECORD1 Trial.

Background Thromboprophylaxis for at least 10 days and for up to 4–5 weeks is recommended after total hip arthroplasty (THA). Rivaroxaban is an oral, direct Factor Xa inhibitor in advanced clinical development for the prevention and treatment of thromboembolic disorders. RECORD1 was a phase III, multinational, randomized, double-blind, double-dummy trial, conducted to determine the efficacy and safety of oral rivaroxaban, compared with subcutaneous enoxaparin, for 5 weeks of thromboprophylaxis in patients undergoing THA.Methods Patients received rivaroxaban 10 mg beginning 6–8 hours after surgery and once daily (od) thereafter, or enoxaparin 40 mg od, beginning the evening before surgery (restarting 6–8 hours after surgery). Therapy continued for 35±4 days and mandatory, bilateral venography was conducted the next day. The primary efficacy endpoint was the composite of any deep vein thrombosis (DVT), non-fatal pulmonary embolism (PE), and all-cause mortality. The primary efficacy analysis was a test for non-inferiority in the per-protocol (PP) population, followed by a test for superiority in the modified intention-to-treat (mITT) population. The main secondary efficacy endpoint was major venous thromboembolism (VTE): the composite of proximal DVT, non-fatal PE and VTE-related death. Major and non-major bleeding during the active treatment period were the primary and secondary safety endpoints, respectively.Results A total of 4541 patients were randomized; 4433 were eligible for the safety population, 3153 for the mITT population, and 3029 for the PP population. The criteria for non-inferiority were met and testing for superiority was performed. Rivaroxaban significantly reduced the incidence of the primary efficacy endpoint (p<0.001) and major VTE (p<0.001), compared with enoxaparin, in the mITT population (Table). The incidence of major and non-major bleeding events was similar in both groups (Table). Conclusions Rivaroxaban was significantly more effective than enoxaparin for extended prophylaxis after THA, with a similar safety profile. This is the first pivotal trial to demonstrate the efficacy and safety of a fixed, unmonitored dose of an oral, direct Factor Xa inhibitor - rivaroxaban - for extended thromboprophylaxis after THA.Rivaroxaban 10mg od % (n/N)Enoxaparin 40 mg od % (n/N)Relative risk reduction % (95% CI)P-value for differenceDVT, non-fatal PE, and all-cause mortality1.1% (18/1595)3.7% (58/1558)70% (49–82%)P<0.001Major VTE0.2% (4/1686)2.0% (33/1678)88% (66–96%)P<0.001Major bleeding0.3% (6/2209)0.1% (2/2224)-P=0.178Non-major bleeding5.8% (128/2209)5.8% (129/2224)-P=1.000

Extended Thromboprophylaxis with Rivaroxaban Compared with Short-Term Thromboprophylaxis with Enoxaparin after Total Hip Arthroplasty: The RECORD2 Trial.

Venous thromboembolism (VTE) is a common, potentially fatal complication of major orthopaedic surgery. Pharmacologic thromboprophylaxis is recommended for patients undergoing total hip arthroplasty (THA) for a minimum of 10 days, and up to 35 days. However, extended thromboprophylaxis is not universally used. Therefore, this trial was conducted to evaluate the potential benefits of extended thromboprophylaxis after THA. RECORD2 is the largest, prospective, randomized clinical trial conducted to date, in this indication. This global, phase III, double-blind trial, was designed to compare short-term thromboprophylaxis with a low molecular weight heparin - enoxaparin - with extended thromboprophylaxis for up to 5 weeks with a novel, oral, direct Factor Xa inhibitor - rivaroxaban after THA. Patients received subcutaneous enoxaparin 40 mg once daily (od), beginning the evening before surgery, continuing for 10–14 days (short-term prophylaxis), and followed by placebo until day 35±4, or oral rivaroxaban 10 mg od beginning 6–8 hours after surgery and continuing for 35±4 days (extended prophylaxis). Mandatory, bilateral venography was conducted at the end of the extended treatment period. The primary efficacy endpoint was the composite of any deep vein thrombosis (DVT), non-fatal pulmonary embolism (PE), and all-cause mortality. The main secondary efficacy endpoint was major VTE; the composite of proximal DVT, non-fatal PE, and VTE-related death. Major and non-major bleeding during double-blind treatment were the primary and secondary safety endpoints, respectively. A total of 2509 patients were randomized; 2457 were included in the safety population and 1733 in the modified intention-to-treat (mITT) population. Extended thromboprophylaxis with rivaroxaban was associated with a significant reduction in the incidence of the primary efficacy endpoint and major VTE, compared with short-term thromboprophylaxis with enoxaparin (Table). The incidences of major and non-major bleeding were similar in both groups (Table). In conclusion, extended duration rivaroxaban was significantly more effective than short term enoxaparin for the prevention of VTE, including major VTE, in patients undergoing THA. Furthermore, this large trial demonstrated that extended thromboprophylaxis provides substantial benefits for patients undergoing THA, and that the oral, direct Factor Xa inhibitor rivaroxaban provides a safe and effective option for such a strategy.Short-term s.c. enoxaparin 40 mg od % (n/N)Extended oral rivaroxaban 10 mg od % (n/N)Relative risk reduction (%)P-value for differenceDVT, non-fatal PE, and all-cause mortalitya9.3% (81/869)2.0% (17/864)79%P<0.001Major VTEb5.1% (49/962)0.6% (6/961)88%P<0.001Major bleedingc0.1% (1/1229)0.1% (1/1228)-P=0.980Non-major bleedingc5.5% (67/1229)6.5% (80/1228)-P=0.246

Fentanyl HCl iontophoretic transdermal system versus intravenous morphine pump after gynecologic surgery

To compare the efficacy and safety of fentanyl iontophoretic transdermal system (ITS) with morphine intravenous patient-controlled analgesia (IV PCA) for pain management following gynecologic surgery. A subgroup (n = 275) of gynecologic surgery patients from a randomized study (N = 636) of patients treated with fentanyl ITS or morphine IV PCA was analyzed. The main efficacy endpoint was the patient global assessment (PGA) of the method of pain control (first 24 h). In gynecologic surgery patients, PGA success ratings (excellent/good) were statistically equivalent (fentanyl ITS, 84.8%; morphine IV PCA, 83.9%; 95% confidence interval: -7.7%, 9.4%) based on the prespecified equivalence criterion of 10% for the entire study population. Pain intensity at 3 h (P = 0.296), discontinuations due to inadequate analgesia (P = 0.148), and percentages of patients requesting supplemental opioids in the first 3 h (P = 0.524) were similar. The two modalities were therapeutically equivalent for pain management in these gynecologic surgery patients.