Optimising cell-based bioassays via integrated design of experiments (ixDoE) - A practical guide.

For process optimisation Design of Experiments (DoE) has long been established as a more powerful strategy than a One Factor at a Time approach. Nevertheless, DoE is not widely used especially in the field of cell-based bioassay development although it is known that complex interactions often exist. We believe that biopharmaceutical manufacturers are reluctant to move beyond standard practices due to the perceived costs, efforts, and complexity. We therefore introduce the integrated DoE (ixDoE) approach to target a smarter use of DoEs in the bioassay setting, specifically in optimising resources and time. Where in a standard practice 3 to 4 separate DoEs would be performed, our ixDoE approach includes the necessary statistical inference from only a single experimental set. Hence, we advocate for an innovative, ixDoE approach accompanied by a suitable statistical analysis strategy and present this as a practical guide for a typical bioassay development from basic research to biopharmaceutical industry.

Does the cognitive measure Cog-4 show improvement among patients treated with thrombolysis after acute stroke?

BACKGROUND: Although the established measure of disability post stroke, the modified Rankin Scale emphasizes motor function and may underestimate the importance of cognitive impairment in more disabled patients. A subset of four items from the National Institutes of Health Stroke Scale has been proposed to assess cognitive function after stroke (Cog-4), and to correlate with modified Rankin Scale. Items correspond to orientation, executive function, language, and inattention. We investigated responsiveness of Cog-4 to treatment with thrombolysis and whether it offers information that supplements modified Rankin Scale. METHODS: We included 6268 patients from the Virtual International Stroke Trials Archive: 2734 received intravenous thrombolysis and 3534 were treated conservatively. We compared day 90 outcomes between treated and untreated groups, by modified Rankin Scale (illustrative) and by Cog-4 (primary measure) adjusting for age, baseline National Institutes of Health stroke scale, hemispheric lateralisation as well as baseline Cog-4 and baseline National Institutes of Health Stroke Scale excluding baseline Cog-4 separately. Analysis of Cog-4 was repeated within strata of 90 day modified Rankin Scale. Statistical analyses included proportional odds logistic regression and Cochran-Mantel-Haenszel test. RESULTS: Modified Rankin Scale showed a difference between treatment groups of expected magnitude (odds ratio 1·56; 95% confidence interval 1·43-1·72; P < 0·001). After adjustment for imbalance in baseline prognostic factors, the distribution of Cog-4 scores at 90 days was better in thrombolysed patients compared with nonthrombolysed patients (odds ratio 1·31; 95% confidence interval 1·18-1·47; P = 0·006). However, Cog-4 analysis stratified by 90-day modified Rankin Scale was neutral between treatment groups (OR 1·01; 95% CI 0·90-1·14), and Cog-4 was not responsive to treatment group even within modified Rankin Scale categories 4 and 5 despite substantial cognitive deficits in these patients. CONCLUSION: Although Cog-4 may be responsive to treatment effects, it does not provide additional information beyond modified Rankin Scale assessment.

The Virtual International Stroke Trials Archive (VISTA): results and impact on future stroke trials and management of stroke patients.

BACKGROUND: The Virtual International Stroke Trials Archive was established to improve stroke care and trial design through the collation, categorization and potential access to data sets from clinical trials for the treatment of stroke. METHODS: Virtual International Stroke Trials Archive currently provides access to a combined data set of 29 anonymised acute stroke trials and one acute stroke registry with data on >27,500 patients aged between 18 and 103 (mean 71) years. RESULTS: Virtual International Stroke Trials Archive has facilitated research across a broad canvas. The prognosis was poor in patients with very high blood pressure at the time of admission or with a wide variability of systolic blood pressure during the acute phase. The late occurrence of hyperthermia following an ischaemic stroke worsens the prognosis. Stroke lateralisation is not an important predictor of cardiac adverse events or 90-day mortality. Haemorrhagic transformation is seen frequently in patients with cardio-embolic strokes and is associated with a poor prognosis when occurring after the acute phase. Virtual International Stroke Trials Archive has allowed various prognostic models for patients with ischaemic or haemorrhagic stroke to be established and validated. More direct outcomes such as lesion volume can be useful in phase II clinical trials for determining whether a phase III trial should be undertaken. New outcome measures such as 'home time' may also strengthen future trials. On a worldwide level, the prognosis of stroke patients differs considerably between various countries. CONCLUSION: Virtual International Stroke Trials Archive provides an excellent opportunity for analysis of natural history data and prognosis. It has the potential to influence clinical trial design and implementation through exploratory data analyses.

International multicentre trial protocol to assess the efficacy and safety of tenecteplase during cardiopulmonary resuscitation in patients with out-of-hospital cardiac arrest: the Thrombolysis in Cardiac Arrest (TROICA) Study.

Prehospital cardiac arrest has been associated with a very poor prognosis. Acute myocardial infarction and massive pulmonary embolism are the underlying causes of out-of-hospital cardiac arrest in 50-70% of patients. Although fibrinolysis is an effective treatment strategy for both myocardial infarction and pulmonary embolism, clinical experience for this therapy performed during resuscitation has been limited owing to the anticipated risk of severe bleeding complications. The TROICA study is planned as one of the largest randomized, double-blind, placebo-controlled trials to assess the efficacy and safety of prehospital thrombolytic therapy in cardiac arrest of presumed cardiac origin. Approximately 1000 patients with cardiac arrest will be randomized at approximately 60 international study centres to receive either a weight-adjusted dose of tenecteplase or placebo after the first dose of a vasopressor. Patients can be included if they are at least 18 years, presenting with a witnessed cardiac arrest of presumed cardiac origin, and if either basic life support had started within 10 min of onset and had been performed up to 10 min or advanced life support is started within 10 min of onset of cardiac arrest. Primary endpoint of the study is the 30-day survival rate, and the coprimary endpoint is hospital admission. Secondary endpoints are the return of spontaneous circulation (ROSC), survival after 24 h, survival to hospital discharge, and neurological performance. Safety endpoints include major bleeding complications and symptomatic intracranial haemorrhage.

Hemorrhagic transformation of ischemic brain tissue: asymptomatic or symptomatic?

BACKGROUND AND PURPOSE: The term symptomatic hemorrhage secondary to ischemic stroke implies a clear causal relationship between clinical deterioration and hemorrhagic transformation (HT) regardless of the type of HT. The aim of this study was to assess which type of HT independently affects clinical outcome. METHODS: We used the data set of the European Cooperative Acute Stroke Study (ECASS) II for a post hoc analysis. All patients had a control CT scan after 24 to 96 hours or earlier in case of rapid and severe clinical deterioration. HT was categorized according to radiological criteria: hemorrhagic infarction type 1 and type 2 and parenchymal hematoma type 1 and type 2. The clinical course was prospectively documented with the National Institutes of Health Stroke Scale and the modified Rankin Scale: The independent risk of each type of HT was calculated for clinical deterioration at 24 hours and disability and death at 3 months after stroke onset and adjusted for possible confounding factors such as age, severity of stroke syndrome at baseline, and extent of the ischemic lesion on the initial CT. RESULTS: Compared with absence of HT, only parenchymal hematoma type 2 was associated with an increased risk for deterioration at 24 hours after stroke onset (adjusted odds ratio, 18; 95% CI, 6 to 56) and for death at 3 months (adjusted odds ratio, 11; 95% CI, 3.7 to 36). All other types of HT did not independently increase the risk of late deterioration. CONCLUSIONS: Only parenchymal hematoma type 2 independently causes clinical deterioration and impairs prognosis. It has a distinct radiological feature: it is a dense homogeneous hematoma >30% of the ischemic lesion volume with significant space-occupying effect.

Comparison of intramuscular and oral meloxicam in rheumatoid arthritis patients.

OBJECTIVE: This double-blind, double-dummy, two-way comparative trial evaluated the overall efficacy and tolerability of intramuscular (im) vs oral meloxicam. SUBJECTS: 346 patients with rheumatoid arthritis (RA). TREATMENT AND METHODS: 173 patients in each group were randomised to receive either im meloxicam (15 mg) plus a placebo tablet, or oral meloxicam (15 mg) plus a placebo injection for 7 days. RESULTS: Significant (p < 0.001) improvements in overall pain and disease activity were observed by patients treated with im and oral meloxicam, with no significant difference between treatments. The im formulation was better than the oral tablet in terms of rapidity of action (p=0.012), global efficacy (p=0.030) and duration of morning stiffness (p=0.026). Local tolerability of im meloxicam was very good and comparable with placebo injections. CONCLUSION: Oral and im meloxicam (15 mg) were both effective and well-tolerated for acute exacerbations of RA. The im formulation had some advantages, such as a faster onset of action.

Meloxicam: a review of its pharmacokinetics, efficacy and tolerability following intramuscular administration.

This paper reviews published studies on the intramuscular use of meloxicam in acute rheumatic conditions. Data were obtained from 68 healthy volunteers and >800 patients with conditions such as arthritis, sciatica and lumbago who were treated with intramuscular injections of meloxicam compared with oral formulations. Intramuscular meloxicam appears to have a more rapid onset of action than oral meloxicam in acute inflammatory rheumatism. Local tolerance of im meloxicam was consistently good in both volunteers and patients, with respect to creatine phosphokinase levels and local reactions. Meloxicam im was also superior to other drugs such as piroxicam with respect to local tolerance. The incidence of adverse events, including gastrointestinal events, was low. Therefore, im meloxicam is an alternative to achieve rapid relief of acute pain in patients with acute inflammatory rheumatism. However, the recurrent use of im meloxicam is not recommended and patients should be switched to the oral formulation for chronic use.

Bootstrap statistics of ECASS II data: just another post hoc analysis of a negative stroke trial?

UNLABELLED: The results of the Second European-Australasian Acute Stroke Study (ECASS II) were negative with respect to the primary endpoint. This post hoc analysis of ECASS II data was designed to make the least number of a priori assumptions. This is accomplished by a bootstrap-based hypothesis test on a non-parametric test statistic. No assumptions are made on shape or variance of population distributions and the method does not suffer from the disadvantages of dichotomization. By reducing the number of a priori assumptions, the possibilities to modify the test result by adjusting the test procedure are minimized. RESULTS: If rt-PA does not improve the outcome (null hypothesis), the probability of observing a difference of modified ranking scale equal or larger than the one observed in ECASS II is 0.047. We therefore rejected the null hypothesis.

Risk factors for severe hemorrhagic transformation in ischemic stroke patients treated with recombinant tissue plasminogen activator: a secondary analysis of the European-Australasian Acute Stroke Study (ECASS II).

BACKGROUND AND PURPOSE: Intravenous thrombolysis with recombinant tissue plasminogen activator (rtPA) improves the outcome for ischemic stroke patients who can be treated within 3 hours of symptom onset. The efficacy of thrombolysis has been demonstrated despite an increased risk of severe hemorrhagic transformation (HT) in patients treated with rtPA. We performed an analysis of risk factors for severe HT in the second European-Australasian Acute Stroke Study (ECASS II). METHODS: HTs were classified by using clinical and radiological criteria as follows: hemorrhagic infarction (HI), parenchymal hemorrhage (PH), and symptomatic intracranial hemorrhage (SICH). Potential risk factors for HT were tested by stepwise logistic regression analysis, including rtPA-by-variable interactions. In addition, the distribution of bad outcome (modified Rankin score 5 to 6) at day 90 was stratified according to each category of HT. RESULTS: PH and SICH but not HI were associated with rtPA. Also, PH and SICH but not HI were more severe in rtPA-treated patients than in those receiving placebo. Risk factors for PH were rtPA, extent of parenchymal hypoattenuation on baseline CT, congestive heart failure, increasing age, and baseline systolic blood pressure. The risk of PH on rtPA was increased in older patients and in those who were treated with aspirin before thrombolysis. Risk factors for SICH were rtPA, congestive heart failure, extent of parenchymal hypoattenuation, and increasing age. The risk of SICH on rtPA was increased in patients who were treated with aspirin before thrombolysis. CONCLUSIONS: This secondary analysis of ECASS II has confirmed the importance of the extent of hypoattenuation as a risk factor for severe HT. The findings also suggest that older patients and those who have used aspirin before stroke are at higher risk of a severe HT on rtPA.

Determination of a weight-adjusted dose of TNK-tissue plasminogen activator.

BACKGROUND: TNK-tissue plasminogen activator (TNK-tPA) is a potent new thrombolytic agent for treatment of acute myocardial infarction. TNK-tPA was evaluated in 4214 patients in two dose-ranging trials (Thrombolysis in Myocardial Infarction [TIMI] 10B and Assessment of the Safety and Efficacy of a New Thrombolytic Agent [ASSENT] I). This article describes the rationale for the weight-adjusted dosing regimen of TNK-tPA that was selected for evaluation in the large phase III clinical trial ASSENT II. METHODS: Weight-based analyses were conducted with data from both the angiographic TIMI 10B trial, which compared TNK-tPA in doses of 30 mg, 40 mg, and 50 mg with the accelerated regimen of tPA in 889 patients, and the ASSENT I trial, which evaluated the safety of TNK-tPA in doses of 30 mg, 40 mg, and 50 mg in 3301 patients. Graphic and statistical analytic methods were used to assess relationships between weight and efficacy or safety measurements. RESULTS: The plasma clearance, initial plasma concentrations, and plasma steady-state volume of distribution all increased with decreasing body weight (all P<.001). The corrected TIMI frame count decreased (flow was faster) (P =.001) and the TIMI grade 3 flow increased with an increasing weight-standardized dose of TNK-tPA (P<.008). Mortality was inversely related to dose, but this relationship was not statistically significant. There was no clear relationship between intracranial hemorrhage and dose and weight. Serious bleeding events increased with increasing weight-standardized dose (P<.02). CONCLUSIONS: On the basis of these analyses, a weight-adjusted dosing regimen was devised for TNK-tPA that included five dosing increments and was based on a target weight-standardized dose of 0.53 mg/kg.

[Neurological scales as endpoints in stroke studies. Aspects of statistical evaluation]. / Neurologische Skalen als Endpunkte in Schlaganfallstudien. Aspekte der statistischen Auswertung.

Even after publication of ECASS II, the latest paper in a series of large, placebo-controlled studies on thrombolysis in acute ischaemic stroke, there is still uncertainty as to what the best clinical endpoint(s) is (are) in trial design for reliably identifying significant differences between treatment groups. If the expected treatment difference as measured by a neurological outcome scale like the Modified Rankin Scale corresponds more to a shift in dispersion (on average a majority of patients profits greatly) rather than to a shift in location (on average each patient profits much), then the power of the odds ratio test is much higher than that of the Wilcoxon test and therefore the clinical outcome parameters should be dichotomised. With respect to the time window of 0-6 hrs from symptom onset of an acute ischaemic stroke, for example, a dichotomisation of 0-2 vs. 3-6 for the Modified Rankin Scale is reasonable. In the case of multiple endpoints, a global (multivariate) test should be used, but the correlation between these endpoints must not be too high, which means that the various manifestations of the complex stroke disease should be considered.

Safety assessment of single-bolus administration of TNK tissue-plasminogen activator in acute myocardial infarction: the ASSENT-1 trial. The ASSENT-1 Investigators.

BACKGROUND: To evaluate the safety of several doses of a new thrombolytic, TNK tissue-plasminogen activator (tPA), given as a single bolus to patients with acute myocardial infarction. METHODS AND RESULTS: A total of 3235 patients were given TNK-tPA: 1705 received 30 mg, 1457 received 40 mg, and 73 received 50 mg. The 50-mg dose was discontinued and replaced by 40 mg because of increased bleeding observed in the Thrombolysis In Myocardial Infarction (TIMI)-10B study, the phase II angiographic efficacy trial conducted in parallel with this study. The total stroke rate at 30 days in the trial was 1.5%. An intracranial hemorrhage was observed in 25 patients (0.77%): 16 in the 30-mg group (0.94%) and 9 in the 40-mg group (0.62%). No strokes occurred in the 73 patients treated with 50 mg TNK-tPA. In patients treated within 6 hours after symptom onset the rates of intracranial hemorrhage were 0.56% (30 mg TNK-tPA) and 0.58 (40 mg TNK-tPA). Death, death or nonfatal stroke, or severe bleeding complications occurred in a low proportion of patients: 6.4%, 7.4%, and 2.8%, respectively, without significant differences among the treatment groups. CONCLUSIONS: The overall safety profile of a single bolus of 30 to 50 mg TNK-tPA is comparable to that of accelerated r-tPA observed in other large trials. The safety data from this trial and the patency data of TIMI-10B were the basis for a decision to conduct a large phase III mortality trial comparing weight-adjusted single-bolus TNK-tPA with accelerated r-tPA (ASSENT-2).

Randomised double-blind placebo-controlled trial of thrombolytic therapy with intravenous alteplase in acute ischaemic stroke (ECASS II). Second European-Australasian Acute Stroke Study Investigators.

BACKGROUND: Thrombolysis for acute ischaemic stroke has been investigated in several clinical trials, with variable results. We have assessed the safety and efficacy of intravenous thrombolysis with alteplase (0.9 mg/kg bodyweight) within 6 h of stroke onset. METHODS: This non-angiographic, randomised, double-blind, trial enrolled 800 patients in Europe, Australia, and New Zealand. Computed tomography was used to exclude patients with signs of major infarction. Alteplase (n=409) and placebo (n=391) were randomly assigned with stratification for time since symptom onset (0-3 h or 3-6 h). The primary endpoint was the modified Rankin scale (mRS) at 90 days, dichotomised for favourable (score 0-1) and unfavourable (score 2-6) outcome. Analyses were by intention to treat. FINDINGS: 165 (40.3%) alteplase-group patients and 143 (36.6%) placebo-group patients had favourable mRS outcomes (absolute difference 3.7%, p=0.277). In a posthoc analysis of mRS scores dichotomised for death or dependency, 222 (54.3%) alteplase-group and 180 (46.0%) placebo-group patients had favourable outcomes (score 0-2; absolute difference 8.3%, p=0.024). Treatment differences were similar whether patients were treated within 3 h or 3-6 h. 85 (10.6%) patients died, with no difference between treatment groups at day 90+/-14 days (43 alteplase, 42 placebo). Symptomatic intracranial haemorrhage occurred in 36 (8.8%) alteplase-group patients and 13 (3.4%) placebo-group patients. INTERPRETATION: The results do not confirm a statistical benefit for alteplase. However, we believe the trend towards efficacy should be interpreted in the light of evidence from previous trials. Despite the increased risk of intracranial haemorrhage, thrombolysis with alteplase at a dose of 0.9 mg/kg in selected patients may lead to a clinically relevant improvement in outcome.

[Systemic thrombolysis with plasminogen activator in chronic stroke patients]. / Systemische Thrombolyse mit Plasminogenaktivator bei alten Schlaganfallpatienten.

Following the study protocol, we stratified the 615 patients of ECASS I according age (< or =/-70 years) and analysed the response to intravenous rt-PA in both subgroups. The older patients (248) suffered from the same stroke severity as the younger patients (367) experienced, however, a more severy clinical course (placebo group after 3 months after stroke: Barthel Index 50 vs. 85, mortality 24% vs. 11%). Treatment with rt-PA increased the proportion of undisabled patients at 3 months after stroke onset significantly only in the younger patients. The risk for brain parenchymal hemorrhage was increased by the factor of 4.7 and 4.6 in both age groups. It is obviously harder to achieve an undisabled state by systemic thrombolysis in the elderly. Facing the risk of brain hemorrhage associated with rt-PA, the risk-benefit-ratio may be less favourable in patients over 70 years.

Dichotomized efficacy end points and global end-point analysis applied to the ECASS intention-to-treat data set: post hoc analysis of ECASS I.

BACKGROUND AND PURPOSE: It is not yet known which end points are the most suitable for evaluation of the effects of acute stroke intervention. The European Cooperative Acute Stroke Study (ECASS) I study used 2 primary end points. The study was powered to detect a 15% improvement of the median of each primary end point. The study failed to show this effect and was negative in the intention-to-treat analysis. The National Institute of Neurological Disorders and Stroke (NINDS) study used 4 dichotomized end points and applied a global end-point analysis. This study was positive and led to FDA approval of thrombolytic therapy for acute ischemic stroke. This study was undertaken to answer the question of whether a different statistical design may have shown a positive results of the ECASS I trial. METHODS: We performed a retrospective analysis of the ECASS I intention-to-treat data set (615 randomized and treated patients, rtPA treatment versus placebo) and post hoc application of the NINDS trial statistical methodology (global end-point analysis). The scores of the modified Rankin Scale (mRS), Barthel Index (BI), and the National Institutes of Health Stroke Scale (NIHSS) were dichotomized according to the criteria used in the NINDS trial. Favorable outcome was defined as a score of 0 or 1 on mRS, a score of 95 or 100 on BI, and a score of 0 or 1 on NIHSS. RESULTS: The number of patients reaching favorable outcome were higher in all 3 end points in the rtPA-treated group. The effect sizes were 8% for mRS, 6% for BI, and 14% for NIHSS, respectively. The differences are statistically significant for the mRS (P=0.044; odds ratio [OR], 1. 4; 95% confidence interval [CI], 1.0 to 2.0) and the NIHSS (P=0.001; OR, 1.9; 95% CI, 1.4 to 2.8), while for the BI significance was missed (P=0.102; OR, 1.3; 95% CI, 0.9 to 1.8). The global end-point statistics, however, shows a significant increase (P=0.008; OR, 1.5; 95% CI, 1.1 to 2.0) of favorable outcome in the rtPA-treated patient group. CONCLUSIONS: Using the global end-point analysis, ECASS is positive in the intention-to-treat analysis. This may indicate that the time window for thrombolysis may be as long as 6 hours. Looking at the 3 dichotomized end points, the effect sizes for 2 end points, mRS and BI, are smaller in the ECASS 6-hour intention-to-treat population compared with the NINDS trial, whereas the effect size for the NIHSS is larger. While in the NINDS trial all 3 end points reveal statistically significant results, in ECASS only 2 of the 3 corresponding end points, mRS and NIHSS, were statistically significant. This finding underlines an important difference of a global end-point approach: it may show a positive overall result although one of the end points is not positive.

The ECASS 3-hour cohort. Secondary analysis of ECASS data by time stratification. ECASS Study Group. European Cooperative Acute Stroke Study.

OBJECTIVES: (1) To determine whether and how outcome measurements in the ECASS trial are influenced by a shorter time window (0-3 vs. 3-6 h) between onset of symptoms and start of thrombolytic therapy using recombinant tissue plasminogen activator (rt-PA) in acute ischemic stroke. (2) To discuss the results of the ECASS 0- to 3-hour cohort with the results of the National Institute of Neurological Disorders and Stroke Study (NINDSS). DESIGN AND ANALYSIS: Analysis of the 0- to 3-hour and the 3- to 6-hour cohort in accordance with the ECASS protocol. Comparative analysis of the ECASS and NINDSS results following the NINDSS protocol using dichotomized endpoints. MAIN OUTCOME MEASURES: Primary endpoints: modified Rankin Scale, Barthel Index; secondary endpoints: combined Barthel/Rankin, long-term Scandinavian Stroke Scale, National Institutes of Health Stroke Scale, mortality at 30 and 90 days, occurrence of intracranial hemorrhage. NINDS trial endpoint: favorable outcome as defined in the NINDS trial. RESULTS: In ECASS, 87 patients were randomized within 3 h of stroke onset. Differences in favor of rt-PA treatment can be found for all primary and secondary outcome measures in the ECASS 0- to 3-hour cohort, except for mortality at day 30, which is somewhat higher in the rt-pA-treated group. However, due to the small sample size, the differences do not reach statistical significance. Early infarct signs (as defined by the ECASS protocol) are found as early as 2 h after stroke onset. Parenchymal hemorrhages are found significantly more often among rt-PA-treated patients. The results in the ECASS 0- to 3-hour cohort fit well with the results in NINDSS. CONCLUSION: Data from the 3-hour ECASS cohort support the efficacy of early thrombolytic therapy in acute hemispheric stroke patients. Comparing bleeding complications between the ECASS and NINDSS is difficult because of differences in the definition and occurrence of hemorrhagic events.

A double-blind, randomized, placebo-controlled study of efficacy and tolerance of meloxicam treatment in patients with osteoarthritis of the knee.

Meloxicam is a new non-steroidal anti-inflammatory drug (NSAID), with a favourable ratio of inhibition of cyclooxygenase-2 (COX-2)/cyclooxygenase-1 (COX-1), giving the drug the potential to produce few gastric adverse effects. The aim of this study was to investigate the efficacy and safety of meloxicam in patients with osteoarthritis (OA) of the knee. Five hundred and thirteen patients were treated in a double-blind trial comparing once-daily meloxicam 7.5 mg, 15mg, 30mg, or placebo (140, 134, 102 and 137 patients, respectively). Outcome measures included scores on Visual Analogue Scales (VAS) for pain on movement (primary endpoint) and pain at rest in the target joint as well as global efficacy. Lesquesne's index of severity and paracetamol consumption were also measured. Global tolerability and the occurrence of adverse events were monitored. Both meloxicam 7.5 mg and 15 mg were significantly more effective than placebo with respect to pain on movement (p < 0.01 and p < 0.03, respectively). Both doses of meloxicam compared favourably with placebo with respect to pain of the target joint at rest, although only the 15 mg dose achieved statistical significance (p < 0.02). Global efficacy showed a significant difference for both doses of meloxicam (p < 0.05 and p < 0.002 for 7.5 mg and 15 mg doses, respectively). Once daily meloxicam 7.5 and 15 mg is effective and well tolerated in the short term symptomatic treatment of OA of the knee.

Acute stroke: usefulness of early CT findings before thrombolytic therapy.

PURPOSE: To determine whether the extent of subtle parenchymal hypoattenuation detected on computed tomographic (CT) scans obtained within 6 hours of ischemic stroke is a factor in predicting patients' response to thrombolytic treatment. MATERIALS AND METHODS: The baseline CT scans of 620 patients, who received either recombinant tissue plasminogen activator (rt-PA) or a placebo, in a double-blind, randomized multicenter trial were prospectively evaluated and assigned to one of three categories according to the extent of parenchymal hypoattenuation: none, 33% or less (small), or more than 33% (large) of the middle cerebral artery territory. The association between the extent of hypoattenuation on the baseline CT scans and the clinical outcome in the placebo-treated and the rt-PA-treated groups after 3 months was analyzed. RESULTS: In 215 patients with a small hypoattenuating area, treatment increased the chance of good outcome. In 336 patients with a normal CT scan and in 52 patients with a large hypoattenuating area, rt-PA had no beneficial effect but increased the risk for fatal brain hemorrhage. CONCLUSION: The response to rt-PA in patients with ischemic stroke can be predicted on the basis of initial CT findings of the extent of parenchymal hypoattenuation in the territory of the middle cerebral artery.

A double-blind, randomized trial to compare meloxicam 15 mg with diclofenac 100 mg in the treatment of osteoarthritis of the knee.

Meloxicam is a new nonsteroidal anti-inflammatory drug (NSAID), which, in animal tests, displays a high potency for anti-inflammatory and analgesic action. The aim of this study was to investigate the efficacy and tolerability of 15 mg meloxicam in comparison with 100 mg slow-release diclofenac in patients with osteoarthritis of the knee. Two hundred and fifty-eight patients were included in the intent-to-treat analysis; these were randomized into two groups to receive either 15 mg meloxicam (N = 128) or 100 mg diclofenac (N = 130) for a period of 6 weeks. The results with respect to efficacy showed a trend in favor of meloxicam regarding pain on movement, global efficacy and paracetamol consumption, although these differences did not reach statistical significance. The most frequently-occurring adverse events in both groups were of a gastrointestinal (GI) nature. However, there was a higher incidence (26 vs 16%) of GI adverse events in the diclofenac group compared with the meloxicam group. Both drugs were well tolerated when assessed by the patients on a visual analog scale (VAS). Thus, 15 mg meloxicam is an effective and well-tolerated therapy for osteoarthritis and compares favorably with diclofenac 100 mg, a well-established treatment for this indication.