A prospective, open-label, non-comparative study of palivizumab prophylaxis in children at high risk of serious respiratory syncytial virus disease in the Russian Federation.

BACKGROUND: Respiratory syncytial virus (RSV) is a leading cause of lower respiratory tract infections (LRTIs) in children globally. Predisposing conditions for the development of serious RSV disease include preterm infants and those with cardiopulmonary illness, including congenital heart disease (CHD) and bronchopulmonary dysplasia (BPD). No vaccine is currently approved for the prevention of RSV infection. It is recommended that children at high risk be prophylactically administered palivizumab, a monoclonal antibody that has been shown in a number of clinical studies to reduce hospitalization rates due to serious RSV infection. The objective of the current study was to determine the safety and effectiveness of palivizumab in preventing serious RSV disease in high-risk children in the Russian Federation. Children at high risk of serious RSV disease (ie, born at ≤ 35 wk gestational age and ≤ 6 mo of age, and/or aged ≤ 24 mo with BPD or hemodynamically significant CHD) were enrolled. Subjects were to receive 3 to 5 monthly injections of palivizumab 15 mg/kg (depending on the month of the initial injection) over the RSV season. The primary endpoint was RSV-related hospitalizations. Adverse events (AEs) were reported through 100 days following the final injection. RESULTS: One hundred subjects received ≥ 1 injection of palivizumab; 94 completed their dosing schedule. There were no RSV hospitalizations or deaths. Six of 7 subjects hospitalized for respiratory/cardiac conditions had an RSV test, which was negative in all cases. Three non-serious AEs (acute intermittent rhinitis and rhinitis, 1 subject; atopic dermatitis, 1 subject) were considered possibly related to palivizumab. All other AEs were mild or moderate and considered not related/probably not related to palivizumab. CONCLUSION: Palivizumab was generally well tolerated and effectively prevented serious RSV infection in a mixed population of high-risk children in the Russian Federation. TRIAL REGISTRATION: ClinicalTrials.gov: NCT01006629.

Comparison of risk factors between preterm and term infants hospitalized for severe respiratory syncytial virus in the Russian Federation.

BACKGROUND: Respiratory syncytial virus (RSV) is a leading cause of lower respiratory tract infection in infants. Preterm birth, in addition to several demographic and environmental factors, increases the risk for development of severe RSV infection. The purpose of this study was to describe differences in risk factors and protective factors between preterm birth (up to 35 weeks' gestational age) and term infants hospitalized for RSV lower respiratory tract infection in the Russian Federation during the 2008-2009 RSV season. METHODS: Infants up to two years of age hospitalized for a lower respiratory tract infection in Moscow, St Petersburg, and Tomsk were tested for RSV. Patient data, including risk factors and protective factors for RSV, were captured at admission. Differences in these factors were compared between preterm and term patients. RESULTS: A total of 519 infants hospitalized for lower respiratory tract infection were included in the study. Of these, 197 infants (182 term and 15 preterm) tested positive for RSV. Of all hospitalizations, 51.7% (15/29) of preterm infants versus 37.1% (182/490) of term infants had confirmed RSV (P = 0.118). Among the RSV-positive patients, preterm infants were more likely to have a lower weight at admission (P = 0.050), be of multiple gestation (P < 0.001), have more siblings (P = 0.013), and have more siblings under the age of eight years (P < 0.007) compared with term patients. The preterm infants were less likely to be breastfed (P < 0.001) and more likely to have older mothers (P = 0.050). CONCLUSION: Compared with term infants, RSV was a more prevalent cause of hospitalization for lower respiratory tract infection in preterm infants. Of infants hospitalized for RSV, preterm infants were more likely to have additional risk factors for severe RSV. These findings suggest that preterm infants may be exposed to a combination of more strongly interrelated risk factors for severe RSV than term infants.

Epidemiology of respiratory syncytial virus in children ≤2 years of age hospitalized with lower respiratory tract infections in the Russian Federation: a prospective, multicenter study.

BACKGROUND: Respiratory syncytial virus (RSV) is the leading cause of severe lower respiratory tract infections among infants and young children, and is responsible for an estimated four million deaths per year globally. A monthly injection of palivizumab has been used for prophylaxis of serious RSV infections among high-risk children in 71 countries since 1998 and approval for use in the Russian Federation was obtained in February 2010. A recommendation for RSV prophylaxis in the Russian Federation would require knowledge of the prevalence and seasonality of RSV in that country. METHODS: In a prospective, multicenter, epidemiological study of the prevalence, seasonality, and peak occurrence of RSV infection, children aged ≤2 years hospitalized for lower respiratory tract infections in three regions of the Russian Federation, from September 2008 through April 2009, were screened and tested for RSV using rapid immunochromatography of nasopharyngeal lavage. For subjects who were tested positive, hospitalization data were collected. RESULTS: Of 519 children aged ≤2 years enrolled from September 11, 2008 through April 26, 2009, 197 tested positive for RSV (38.0%, 95% CI: 33.8, 42.3). The onset of the 2008-2009 RSV season in the Russian Federation occurred in late October 2008, similar to what is observed in other northern temperate zones. Peak activity occurred in early April 2009, when 62% of children enrolled tested positive for RSV. CONCLUSION: The prevalence of serious RSV infections in the Russian Federation is similar to the prevalence previously identified in other temperate zones of the northern hemisphere. The seasonality of disease shifted towards early spring, with peak activity later in the season, within a range reported in other countries. These data provide further evidence of serious RSV infection in children in the Russian Federation, as well as guidance for timing of seasonal RSV prophylaxis, especially among individuals at high risk for serious RSV infection.

Sex-based differences in the effect of intra-arterial treatment of stroke: analysis of the PROACT-2 study.

BACKGROUND AND PURPOSE: Sex influences outcome after intravenous thrombolysis. In a combined analysis of the tissue plasminogen activator clinical trials, a sex-by-treatment interaction was observed. We sought to confirm that observation in an independent data set. METHODS: Data were from the Pro-Urokinase for Acute Cerebral Thromboembolism-2 (PROACT-2) trial. Baseline factors were compared by sex. The primary outcome was an assessment of a sex-by-treatment interaction term within a logistic regression model, using a modified Rankin Scale score

Recombinant urokinase is safe and effective in restoring patency to occluded central venous access devices: a multiple-center, international trial.

BACKGROUND: The treatment of choice for central venous access device (CVAD) occlusion is intracatheter thrombolysis, which has been reported to reestablish patency in up to 80% of cases. However, these salient results have only been achieved in highly selected CVAD subgroups such as nontunneled devices in adult patients, devices with recent occlusion, and in partially occluded devices through which fluid can still be infused (withdrawal occlusions). Less is known about the success of intracatheter thrombolysis in the broader range of CVAD malfunction encountered in clinical practice, especially in those devices that are totally occluded. OBJECTIVE: This multiple-center, open-label study was performed to test the hypothesis that a new recombinant urokinase (r-UK, urokinase alfa) is safe and effective in reestablishing patency in a large unselected cohort of occluded CVADs. METHODS: Pediatric and adult patients with any type of CVAD occlusion of any duration were treated with 5000 IU/mL intracatheter r-UK. Lumen patency was assessed after 5, 15, and 30 mins; a second dose of r-UK was instilled if the catheter remained occluded after 30 mins. RESULTS: A total of 903 r-UK instillations were performed in 878 patients (age range, 16 days to 96 yrs). Overall, instillation of r-UK successfully restored total catheter patency (all treated lumens) to 75% of CVADs (681 of 902). Patency was restored to at least one occluded lumen in 79% of devices (712 of 902). Patency was restored equally in catheters with total occlusion (76%) as in catheters with only withdrawal occlusion (75%). The median +/- sd time to patency was 15 +/- 20.8 mins (range, 5-203 mins). CONCLUSION: The use of a new r-UK, 5000 IU/mL, is safe and effective for the restoration of patency to occluded CVADs.

Recombinant urokinase for restoration of patency in occluded central venous access devices. A double-blind, placebo-controlled trial.

The interval occlusion of central venous access devices (CVADs) remains a significant clinical problem, often requiring re-intervention for catheter exchange or replacement. The purpose of this Phase 3, multi-center, double-blinded study was to test the hypothesis that instillation of recombinant urokinase (r-UK) 5000 IU/ml is superior to placebo in restoring total catheter patency to an unselected cohort of occluded CVADs. After obtaining informed consent, adult and pediatric patients with occluded, non-hemodialysis CVADs of any duration or type were randomized (2 : 1) to receive either r-UK 5000 IU/ml or placebo instilled into all occluded lumens of their catheter. Catheter function was assessed at 5, 15 and 30 min after the first instillation. If the catheter remained occluded after 30 min, a second dose was instilled with repeat assessments at 5, 15 and 30 min. The primary efficacy variable was the restoration of catheter function to all treated lumens (i.e., total catheter patency) after one or two instillations. Catheters that were not successfully recanalized after two instillations were allowed to receive up to two instillations of open-label r-UK administered in the same manner. The primary safety variable was the occurrence of hemorrhagic and non-hemorrhagic events within 72 hr after instillation. A total of 180 patients were enrolled at 43 sites in the United States and Canada. Most patients were adults, although 20% were

Dose-ranging trial with a recombinant urokinase (urokinase alfa) for occluded central venous catheters in oncology patients.

PURPOSE: Recombinant urokinase (r-UK) is a high-molecular-weight urokinase produced in transfected, non-human, mammalian cells. A Phase II, randomized, double-blind, parallel, placebo-controlled, dose-ranging study was performed to compare the safety and efficacy of one or two instillations of three intraluminal concentrations of r-UK (5,000; 15,000; and 25,000 IU/mL) with a placebo for reestablishment of total function to occluded central venous access devices (CVADs). MATERIALS AND METHODS: One-hundred eight patients with CVAD withdrawal or total occlusion were enrolled and randomized to treatment; 104 patients received at least one instillation of study drug and 101 patients completed treatment. All but one patient had cancer. RESULTS: All three concentrations of r-UK were significantly superior to placebo in restoring total CVAD function (patency of all occluded lumens) after one or two instillations of study medication (25,000 IU/mL r-UK, 68% vs. placebo, 28% [P =.007]; 15,000 IU/mL r-UK, 69% vs. placebo, 24% [P =.004]; 5,000 IU/mL r-UK, 70% vs. placebo, 28% [P =.003]). Comparisons of the three r-UK concentrations indicated no difference after one or two instillations with regards to patency restoration. Treatment-emergent hemorrhagic events occurring within 72 hours after study drug exposure were experienced by four patients (17%) in the 25,000 IU/mL r-UK group, two patients (7%) in the 15,000 IU/mL r-UK group, no patients in the 5,000 IU/mL r-UK group, and no patients in the placebo group. CONCLUSIONS: Efficacy and safety results of this study support further evaluation of a 5,000 IU/mL concentration of r-UK for treatment of occluded CVADs in adult and pediatric patients from 1 year of age.

Selection of acute ischemic stroke patients for intra-arterial thrombolysis with pro-urokinase by using ASPECTS.

BACKGROUND: Previous studies have suggested that baseline computed tomographic (CT) scans might be a useful tool for selecting particular ischemic stroke patients who would benefit from thrombolysis. The aim of the present study was to assess whether the baseline CT scan, assessed with the Alberta Stroke Program Early CT Score (ASPECTS), could identify ischemic stroke patients who might particularly benefit from intra-arterial thrombolysis of middle cerebral artery occlusion. METHODS: Baseline and 24-hour follow-up CT scans of patients randomized within 6 hours of symptoms to intra-arterial thrombolysis with recombinant pro-urokinase or control in the PROACT-II study were retrospectively scored by using ASPECTS. Patients were stratified into those with ASPECTS >7 or < or =7. Independent functional outcome at 90 days was compared between the 2 strata according to treatment assignment. RESULTS: The analysis included 154 patients with angiographically confirmed middle cerebral artery occlusion. The unadjusted risk ratio of an independent functional outcome, in favor of treatment, in the ASPECTS >7 group was 5.0 (95% confidence interval [CI], 1.3 to 19.2) compared with 1.0 (95% CI, 0.6 to 1.9) in the ASPECTS < or =7 group. After adjustment for baseline characteristics, the risk ratio in the ASPECTS score >7 was 3.2 (95% CI, 1.2 to 9.1). Similar favorable treatment effects were observed when secondary outcomes were used, but these did not reach statistical significance. CONCLUSIONS: Ischemic stroke patients with a baseline ASPECTS >7 were 3 times more likely to have an independent functional outcome with thrombolytic treatment compared with control. Patients with a baseline ASPECTS < or =7 were less likely to benefit from treatment. This observation suggests that ASPECTS can be both a useful clinical tool and an important method of baseline risk stratification in future clinical trials of acute stroke therapy.

Factors influencing outcome and treatment effect in PROACT II.

BACKGROUND AND PURPOSE: The PROACT II study demonstrated a significant benefit from treatment with intra-arterial pro-urokinase (r-proUK) in patients with middle cerebral artery occlusion treated within 6 hours of stroke onset. The purpose of the current study was to examine baseline factors to determine predictors of good outcome and response to treatment. METHODS: We selected from the baseline clinical, radiologic, and angiographic data variables that considered possibly related to outcome. A univariate analysis was performed to examine the association between these baseline factors and good outcome, defined as a modified Rankin scale score

Computed tomographic findings in patients undergoing intra-arterial thrombolysis for acute ischemic stroke due to middle cerebral artery occlusion: results from the PROACT II trial.

BACKGROUND AND PURPOSE: The purpose of this study was to evaluate the role of noncontrast CT in the selection of patients to receive thrombolytic therapy for acute ischemic stroke and to predict radiological and clinical outcomes. METHODS: One hundred eighty patients with stroke due to middle cerebral artery (MCA) occlusion were randomized 2:1 within 6 hours of onset to receive intra-arterial recombinant prourokinase plus intravenous heparin or intravenous heparin only. Four hundred fifty-four CT examinations were digitized to calculate early infarct changes, infarct volumes, and hemorrhagic changes among the 162 patients treated as randomized (108 recombinant prourokinase-treated patients and 54 control patients). CT changes were correlated with baseline stroke severity, angiographic clot location, collateral vessels, and outcome at 90 days. RESULTS: Baseline CT scans, 120 (75%) of 159, showed early infarct-related abnormalities. The baseline CT abnormality volume was not correlated with the baseline National Institutes of Health Stroke Scale (NIHSS) score (r=-0.11) but was correlated weakly with the outcome (r=0.17, P<0.05). Compared with patients with M2 occlusions, patients with M1 MCA occlusions had significantly higher baseline NIHSS scores (P<0.05), more basal ganglia involvement on CT, and larger hypodensity volumes on follow-up CTs. Compared with patients with partial or no collateral supply, patients with full collateral supply had lower baseline NIHSS scores, significantly smaller baseline CT infarct volumes, and less cortical involvement (P<0.05). CONCLUSIONS: Noncontrast CT is not correlated with baseline stroke severity and does not predict outcome in patients with stroke due to MCA occlusion. However, baseline CT changes, clinical presentation, and the evolution of CT changes are influenced by clot location and the presence of a collateral supply.