Efficacy and safety of BAY 81-8973, a full-length recombinant factor VIII: results from the LEOPOLD I trial.

INTRODUCTION: BAY 81-8973 (Kovaltry(®) ) is a full-length, unmodified recombinant human factor VIII (FVIII) with the same amino acid sequence as sucrose-formulated recombinant FVIII and is produced using additional advanced manufacturing technologies. AIM: To demonstrate efficacy and safety of BAY 81-8973 for treatment of bleeds and as prophylaxis based on two different potency assignments. METHODS: In LEOPOLD I (ClinicalTrials.gov identifier, NCT01029340), males aged 12-65 years with severe haemophilia A and ≥150 exposure days received BAY 81-8973 20-50 IU kg(-1) two or three times per week for 12 months. Potency was based on chromogenic substrate assay per European Pharmacopoeia and label adjusted to mimic one-stage assay potency. Patients were randomized for potency sequence and crossed over potency groups after 6 months, followed by an optional 12-month extension. Primary efficacy endpoint was annualized bleeding rate (ABR). Patients also received BAY 81-8973 during major surgeries. RESULTS: Sixty-two patients received BAY 81-8973 prophylaxis and were included in the analysis. Median ABR was 1.0 (quartile 1, 0; quartile 3, 5.1) without clinically relevant differences between potency periods. Median ABR was similar for twice-weekly vs. three times-weekly dosing (1.0 vs. 2.0). Haemostasis was maintained during 12 major surgeries. Treatment-related adverse event (AE) incidence was ≤7% overall; no patient developed inhibitors. One patient with risk factors for cardiovascular disease developed a myocardial infarction. CONCLUSIONS: BAY 81-8973 was efficacious in preventing and treating bleeding episodes, irrespective of the potency assignment method, with few treatment-related AEs. Caution should be used when treating older patients with cardiovascular risk factors.

BAY 81-8973, a full-length recombinant factor VIII: results from an International comparative laboratory field study.

INTRODUCTION: BAY 81-8973 is a full-length, unmodified, recombinant human factor VIII (FVIII) with the same primary amino acid sequence as sucrose-formulated recombinant FVIII but produced with certain more advanced manufacturing technologies. AIM: This global laboratory study evaluated variability in measurement of BAY 81-8973 using one-stage and chromogenic assays compared with antihaemophilic factor (recombinant) plasma/albumin-free method (rAHF-PFM; Advate(®) ) under assay conditions routinely used in clinical laboratories. METHODS: BAY 81-8973 or rAHF-PFM was spiked into FVIII-deficient plasma at 0.043 (low), 0.375 (medium) and 0.865 (normal) IU mL(-1) . Participating laboratories analysed blinded samples and normal plasma in triplicate using their routine assay, reagents and standards. Results were analysed for intra- and interlaboratory variability. RESULTS: Forty-one laboratories in 11 countries participated in the study. One-stage assay and chromogenic assays were used by 40 and 10 laboratories, respectively; 9 laboratories used both assays. Intralaboratory variability was <11% for both assays and both products at all concentrations. Interlaboratory variability was highest at the low concentration in the chromogenic and one-stage assay for BAY 81-8973 (60.0% and 33.7%, respectively) and rAHF-PFM (51.0% and 30.8%) and was lowest at the normal concentration (BAY 81-8973, 5.4% and 14.0%; rAHF-PFM, 5.8% and 12.4%), which was similar to the plasma control (6.6% and 10.3%). The chromogenic:one-stage assay ratio ranged from 0.95 (low concentration) to 1.10 (normal concentration) for BAY 81-8973 and 0.96-1.18 for rAHF-PFM. CONCLUSIONS: BAY 81-8973 can be accurately measured in plasma using the one-stage and chromogenic assays routinely used in clinical laboratories without a product-specific standard.

Chromogenic assay for BAY 81-8973 potency assignment has no impact on clinical outcome or monitoring in patient samples.

UNLABELLED: Essentials Discrepancies can exist in factor VIII activity measured by the one-stage or chromogenic assays. LEOPOLD trial data were used to assess clinical impact of BAY 81-8973 potency assignment assay. Efficacy was not affected by the assay used for potency assignment and dosing of BAY 81-8973. Either assay may be used to measure factor VIII activity after BAY 81-8973 infusion. SUMMARY: Background Product-specific discrepancies have been reported for factor VIII (FVIII) activity determined with one-stage or chromogenic assays. Objective To assess the clinical impact of potency assignment of BAY 81-8973, a full-length, unmodified, recombinant human FVIII, by use of the chromogenic assay or chromogenic assay adjusted to mimic results obtained with the one-stage assay Patients/methods Patients aged 12-65 years with severe hemophilia A received BAY 81-8973 in LEOPOLD I (20-50 IU kg(-1) two or three times weekly [investigator decision]) and LEOPOLD II (randomized to 20-30 IU kg(-1) twice weekly, 30-40 IU kg(-1) three times weekly, or on-demand treatment). Both trials included two 6-month crossover periods in which potency labeling was determined with the chromogenic substrate assay as per the European Pharmacopoeia (CS/EP) or the chromogenic substrate assay adjusted to mimic results obtained with the one-stage assay (CS/ADJ). The annualized bleeding rate (ABR) and FVIII incremental recovery were assessed by the use of pooled data. Results The analysis was perfomed on 121 patients. Median (quartile [Q] 1; Q3) ABRs during the CS/EP and CS/ADJ periods were 1.98 (0; 5.92) and 1.98 (0; 7.34), respectively. The mean incremental recovery was > 2 IU dL(-1) per IU kg(-1) in both periods with the use of either assay for postinfusion FVIII measurements. The median (Q1; Q3) chromogenic/one-stage assay recovery ratio was 1.054 (0.892; 1.150) for the CS/EP period when a plasma standard was used for calibration. Conclusions No impact on the ABR was observed with chromogenic-based as compared with one-stage assay-based potency and dosing. Either assay may be used to determine FVIII plasma activity after infusion of BAY 81-8973 without the need for a product-specific standard.

Safety and efficacy of BAY 81-8973 for surgery in previously treated patients with haemophilia A: results of the LEOPOLD clinical trial programme.

INTRODUCTION: BAY 81-8973 is a recombinant factor VIII (rFVIII) with the same amino acid sequence as Bayer's sucrose-formulated rFVIII (rFVIII-FS) but manufactured with certain more advanced technologies. AIM: To describe surgery outcomes with BAY 81-8973 in the LEOPOLD trials. METHODS: Male patients with severe haemophilia A and no inhibitors aged 12-65 years with ≥150 exposure days (EDs) to FVIII (LEOPOLD I and II), or aged ≤12 years with ≥50 EDs to FVIII (LEOPOLD Kids), received BAY 81-8973 based on dosing recommendations for rFVIII-FS according to surgical requirements. Haemostasis-related complications, investigator/surgeon assessment of haemostasis, blood loss, need for transfusion and use of BAY 81-8973 were determined. RESULTS: In LEOPOLD I and II, 11 patients (mean age, 35.3 years) underwent 13 major surgeries. In LEOPOLD Kids, one patient (aged 6 years) underwent one major surgery. Thirty-two adult and paediatric patients underwent 46 minor surgeries. Haemostasis was rated good or excellent in all major and minor surgeries. Blood loss during surgery did not exceed expected amounts; blood transfusions were required in three of the 14 major surgeries. For major surgeries in LEOPOLD I and II, patients received a presurgical 50-IU kg(-1) dose of BAY 81-8973; median nominal dose on day of surgery was 7000 IU (107.5 IU kg(-1) ). Total BAY 81-8973 dose was 2500 IU (108.7 IU kg(-1) ) on the day of the only major surgery in LEOPOLD Kids. No haemostasis-related complications were reported. CONCLUSIONS: Haemostatic control with BAY 81-8973 during all surgeries in the LEOPOLD trials was good or excellent, with no haemostasis-related complications.

Prophylaxis vs. on-demand treatment with BAY 81-8973, a full-length plasma protein-free recombinant factor VIII product: results from a randomized trial (LEOPOLD II).

BACKGROUND: BAY 81-8973 is a new full-length human recombinant factor VIII product manufactured with technologies to improve consistency in glycosylation and expression to optimize clinical performance. OBJECTIVES: To demonstrate superiority of prophylaxis vs. on demand therapy with BAY 81-8973 in patients with severe hemophilia A. PATIENTS/METHODS: In this multinational,randomized, open-label crossover study (LEOPOLD II;ClinicalTrials.gov identifier: NCT01233258), males aged 12­65 years with severe hemophilia A were randomized to twice-weekly prophylaxis (20-30 IU kg(-1)), 3-times-weekly prophylaxis (30-40 IU kg(-1)), or on-demand treatment with BAY 81-8973. Potency labeling for BAY 81-8973 was based on the chromogenic substrate assay or adjusted to the one-stage assay. Primary efficacy endpoint was annualized number of all bleeds (ABR). Adverse events (AEs)and immunogenicity were also assessed. RESULTS: Eighty patients (on demand, n = 21; twice-weekly prophylaxis, n = 28; 3-times-weekly prophylaxis, n = 31) were treated and analyzed. Mean ± SD ABR was significantly lower with prophylaxis (twice-weekly, 5.7 ± 7.2; 3-times-weekly, 4.3 ± 6.5; combined, 4.9 ± 6.8) vs. on-demand treatment (57.7 ± 24.6; P < 0.0001, ANOVA). Median ABR was reduced by 97% with prophylaxis (twice-weekly, 4.0;3-times-weekly, 2.0; combined, 2.0) vs. on-demand treatment (60.0). Median ABR was higher with twice-weekly vs. 3-times-weekly prophylaxis during the first 6-month treatment period (4.1 vs. 2.0) but was comparable in the second 6-month period (1.1 vs. 2.0). Few patients reported treatment-related AEs (4%); no treatment-related serious AEs or inhibitors were reported. CONCLUSIONS: Twice weekly or 3-times-weekly prophylaxis with BAY 81-8973 reduced median ABR by 97% compared with on-demand therapy, confirming the superiority of prophylaxis. Treatment with BAY 81-8973 was well tolerated.

Late spontaneous recanalization of a symptomatically occluded internal carotid artery two years after extra-intracranial bypass. Case report and review of the literature.

Spontaneous recanalization of the internal carotid artery (ICA) is rarely observed. Mainly case reports are published. Most often early recanalization occurs within days or weeks and only a few cases of late recanalization months or years after detected occlusion are reported. Symptomatic bilateral ICA occlusion is regarded as an acceptable indication for extra-intracranial (EC-IC) bypass. The authors report on a case with bilateral symptomatic ICA occlusion and EC-IC bypass >2 years prior to detected spontaneous leftsided recanalization. Spontaneous recanalization unmasking a high degree ICA stenosis at the carotid bifurcation allowed a successful subsequent surgical recanalization in this patients. Mechanisms of early and late recanalization as well as treatment options are discussed.

A quantitative dynamical systems approach to differential learning: self-organization principle and order parameter equations.

Differential learning is a learning concept that assists subjects to find individual optimal performance patterns for given complex motor skills. To this end, training is provided in terms of noisy training sessions that feature a large variety of between-exercises differences. In several previous experimental studies it has been shown that performance improvement due to differential learning is higher than due to traditional learning and performance improvement due to differential learning occurs even during post-training periods. In this study we develop a quantitative dynamical systems approach to differential learning. Accordingly, differential learning is regarded as a self-organized process that results in the emergence of subject- and context-dependent attractors. These attractors emerge due to noise-induced bifurcations involving order parameters in terms of learning rates. In contrast, traditional learning is regarded as an externally driven process that results in the emergence of environmentally specified attractors. Performance improvement during post-training periods is explained as an hysteresis effect. An order parameter equation for differential learning involving a fourth-order polynomial potential is discussed explicitly. New predictions concerning the relationship between traditional and differential learning are derived.

A randomized study of sequential intravenous/oral moxifloxacin in comparison to sequential intravenous ceftriaxone/oral cefuroxime axetil in patients with hospital-acquired pneumonia.

BACKGROUND: Empiric treatment of hospital-acquired pneumonia (HAP) should be focused on the suspected pathogens. We evaluated the efficacy and safety of moxifloxacin vs ceftriaxone in patients with HAP without risk of infections with Pseudomonas aeruginosa and other non-fermentative Gram-negative bacteria. PATIENTS AND METHODS: We performed a prospective, randomized, non-blind, multicentric and multinational study to compare the efficacy and safety of moxifloxacin 400 mg IV once daily followed by oral moxifloxacin 400 mg once daily to ceftriaxone 2 g IV once daily followed by oral cefuroxime axetil 500 mg twice daily to treat mild-to-moderate HAP in adult patients requiring initial parenteral therapy. The primary efficacy variable was clinical response 7-10 days after the end of a 7-14-day treatment period, secondary endpoints included clinical and bacteriologic response at different intervals for up to 31 days after treatment. The trial was terminated prematurely due to slow patient recruitment. RESULTS: A total of 161 subjects (87 men, 74 women) between 18 and 95 years of age were enrolled, 120 of whom were eligible for per protocol efficacy analyses (60 each in the moxifloxacin and the comparator groups). Clinical success rates were 87% for moxifloxacin and 83% for the comparator [95% CI (-9.77 to 15.96%)]. The results for secondary endpoints were comparable between groups. Both treatments were safe and well tolerated. CONCLUSION: Moxifloxacin IV/oral can be considered as a possible alternative for the antibiotic treatment of patients with mild-to-moderate nosocomial pneumonia without risk factors for highly resistant microorganisms.

[Will carotid thromboendarterectomy remain competitive? Influence of intraoperative duplex ultrasound quality control]. / Wird die Karotischirurgie konkurrenzfähig bleiben? Einfluss intraoperativer duplexsonographischer Qualitätskontrolle.

BACKGROUND: Thromboendarterectomy (TEA) and stenting are in competition for treatment of carotid artery lesions. Both treatment modalities have to improve significantly. The goal of the study was to evaluate the influence of routine intraoperative duplex ultrasound examination. METHODS: In a continuous prospective study, 575 patients underwent 620 carotid operations. Intraoperative duplex ultrasound examination was performed prior to wound closure: 9.5% had significant contralateral ICA stenoses and 6.7% ICA occlusion; 8.5% presented special lesions. An eversion TEA was performed in 20.5% while 78.5% underwent conventional TEA with patch plasty and graft interposition in 1%. Intraoperative quality control revealed unexpected lesions in 10% requiring immediate repair. RESULTS: The combined morbidity/mortality rate (MMR) of the total series was 2.6%. Women had an elevated risk (4.2%) in comparison to men (1.9%). The risk of elder patients (>75 years, n=151) was remarkably low. The neurological complication rate of the total series was 1.6% and the incidence of major strokes 1.1%. CONCLUSIONS: Routine intraoperative duplex ultrasound examination of the carotid reconstruction allows early diagnosis and immediate correction of morphologic as well as hemodynamic lesions. Competing with stent placement a further reduction of complications of carotid TEA seems to be possible and necessary.

[Cycloid psychoses as atypical manic-depressive disorders. Results of a family study]. / Sind zykloide Psychosen atypische manisch-depressive Erkrankungen? Ergebnisse einer Familienuntersuchung.

BACKGROUND: Whereas a growing body of evidence suggests that cycloid psychoses have to be separated from schizophrenic psychoses, their relations to bipolar affective disorder are less clear. PATIENTS AND METHODS: In a controlled family study, we recruited 46 patients with cycloid psychosis (CP), 33 with manic-depressive illness (MDI), and 27 controls. Three hundred fifty-six of 389 living first-degree relatives were personally examined by experienced psychiatrists blinded to the diagnosis of the index proband. RESULTS: The relatives of CP patients showed significantly lower morbidity risk of functional psychoses than relatives of patients with MDI in Kaplan-Meier life table calculation. The morbidity risk for functional psychoses in relatives of patients with CP did not differ significantly from that in relatives of controls. CONCLUSION: These results suggest that CP are etiologically different from bipolar affective psychoses and cannot be integrated into the spectrum of bipolar affective disorders. The findings provide further evidence for a nosological independence of CP.

Cycloid psychoses are not part of a bipolar affective spectrum: results of a controlled family study.

BACKGROUND: Whereas a growing body of evidence suggests that cycloid psychoses have to be separated from schizophrenic psychoses, their relations to bipolar affective disorder are less clear. To further clarify this issue a controlled family study was undertaken. METHODS: All living and traceable adult first-degree relatives of 45 cycloid psychotic, 32 manic-depressive and 27 control probands were personally examined by an experienced psychiatrist blind to the diagnosis of the index proband. Data about not traceable relatives were collected by the "Family-History"-Method. A catamnestic diagnosis was established for each of the 431 relatives blind to family data. Age-corrected morbidity risks were calculated using the life-table method. RESULTS: Relatives of cycloid psychotic patients showed a significantly lower morbidity risk for endogenous psychoses in general and manic-depressive illness compared to relatives of patients with manic-depressive illness. The familial morbidity risk for cycloid psychoses was low and did not differ significantly in both proband groups. Relatives of cycloid psychotic patients however did not differ significantly from relatives of controls regarding familial morbidity. LIMITATIONS: Our time-consuming methodical procedure implicated a relatively small number of participants due to restricted personnel resources. The restriction to hospitalised probands could possibly cause a limited representativity of the study sample. CONCLUSIONS: Our results suggest that cycloid psychoses are aetiologically different from manic-depressive illness and could not be integrated into a spectrum of bipolar affective disorders. The findings provide further evidence for a nosological independence of cycloid psychoses.

(r)-, but not (s)-alpha lipoic acid stimulates deficient brain pyruvate dehydrogenase complex in vascular dementia, but not in Alzheimer dementia.

In dementia of Alzheimer type (DAT), cerebral glucose metabolism is reduced in vivo, and enzymes involved in glucose breakdown are impaired in post-mortem brain tissue. Pyruvate dehydrogenase complex activity (PDHc) is one of the enzymes known to be reduced, while succinate dehydrogenase activity (SDH), another enzyme of oxidative glucose metabolism is unchanged. In dementia of vascular type (DVT), variable changes in glucose metabolism have been demonstrated in vivo, while changes of enzyme activities in post-mortem brain tissue are unknown. Here, PDHc and SDH activity were stimulated with each of the two stereoisomers of alpha lipoic acid in post-mortem parietal brain cortex of patients with DAT, DVT, and one case of Pick's disease and compared to stimulation effects in a control group, matched for age, sex, post-mortem delay, and storage time of brain tissue. PDHc in DAT and DVT, but not in Pick's disease was reduced. PDHc activity could be slightly stimulated by 10 micro M of the physiological stereoisomer (r)-alpha-lipoic acid, in controls and DVT (possibly also in Pick's disease), but not in DAT. In all groups investigated SDH was activated by 100 micro M and 1 mM of both isomers of alpha-lipoic acid, whereas 10 mM of both stereoisomers of alpha-lipoic acid caused an inhibition of both, PDHc and SDH activity. The loss of basal and of (r)-alpha-lipoic acid stimulated PDHc activity indicate that a functional or structural impairment of PDHc may exist in DAT and DVT which is not merely attributable to loss of mitochondria since basal and stimulated SDH activities are similar in controls, DVT and DAT, thus indicating selective vulnerability of PDHc.

Peripheral deposition of alpha1-protease inhibitor using commercial inhalation devices.

Patients with hereditary alpha1-proteinase inhibitor (alpha1-PI) deficiency are at risk of developing lung emphysema. To prevent the development of this disease, alpha1-PI replacement therapy via inhalation may be a more convenient and effective therapy than the intravenous administration of the drug. In order to optimise this treatment approach, lung deposition of inhaled radiolabelled alpha1-PI (Prolastin) was studied using four different commercial inhalation devices (PARI-LC Star, HaloLite, and AKITA system in combination with LC Star and Sidestream) in six patients with alpha1-PI deficiency and mild-to-severe chronic obstructive pulmonary disease. The time required to deposit 50 mg of the Prolastin (5% solution) in the lung periphery was used as a measure for the efficiency of delivery. The time was calculated from measurements of total and peripheral lung deposition of the radiolabelled alpha1-PI. This time was shortest for the AKITA system (18-24 min) and significantly higher for the PARI-LC Star (44 min) and the HaloLite (100 min). The higher efficiency of drug delivery using the AKITA system is due to the fact that this device controls breathing patterns, which are optimised for each patient individually.

Granule cells of the dentate gyrus with basal and recurrent dendrites in schizophrenic patients and controls. A comparative Golgi study.

We report on structural variability of granule cells in the human dentate gyrus. Granule cells with basal and recurrent dendrites are a normal finding in the human brain. We detect 28.3% granule cells with basal dendrites in non-psychiatrically ill humans compared to rats (2%) and primates (10%). This can be seen as an indication for the higher phylogeny of the human brain. In addition we find a significantly higher incidence of granule cells with basal dendrites (45.7%) in brains of schizophrenic patients. Whereas drug influences during lifetime cannot fully be excluded, we tend to interpret this finding as a plastic reaction to prenatal developmental malformations of the impinging rostral entorhinal region.

Pulmonary deposition of monodisperse aerosols in patients with chronic obstructive pulmonary disease.

In order to improve patient convenience and drug availability for patients with alpha 1-protease inhibitor deficiency, the administration via the inhalation route has been considered. This study investigated if it is possible to obtain high values of peripheral aerosol deposition by using optimized and controlled inhalation conditions. Therefore, peripheral deposition was studied in 10 patients with alpha 1-protease inhibitor deficiency (phenotype PiZ) and moderate to severe chronic obstructive pulmonary disease by measuring the 24-hour Clearance of radiolabeled inert iron oxide particles with diameters of 2 microns, 3 microns, and 4 microns. Patients inhaled a large volume of aerosol (1000 to 2000 cm3), which was normalized to the individual lung function, with a flow rate of 200 cm3/S. Due to this breathing pattern, peripheral deposition was for all particle sizes above 50% of the inhaled aerosol. The highest peripheral deposition (68%) was found for 3-microns particles.

Norepinephrine transporter gene (NET) variants in patients with panic disorder.

Several lines of evidence suggest that catecholamines, especially norepinephrine, are implicated in the etiology and/or symptomatology of panic disorder (PD). At the cellular level, functional noradrenergic neurotransmission depends on synaptic reuptake of norepinephrine as mediated by the norepinephrine transporter (NET). A pharmacological target of agents with an established anti-panic efficacy, e.g. tricyclic antidepressants, the NET is of particular interest in PD. We investigated the NET gene for the presence of 6 naturally occurring exonic sequence variants, 5 of which give rise to amino acid substitutions (Val69Ile, Thr99Ile, Val245Ile, Val449Ile and Gly478Ser) in a population of 87 patients with PD and 89 healthy controls. Except for a silent substitution (G1287A), overall frequencies of variant alleles were low (< or =0.016). None of the variants under study was found to be associated with PD regardless of an additional diagnosis of agoraphobia.

Risk assessment in patients with ruptured abdominal aortic aneurysms.

OBJECTIVES: Surgery of ruptured abdominal aortic aneurysms is associated with a high mortality rate, mostly related to multi-organ-failure after a prolonged intensive care therapy. In a retrospective study attempts are made to identify individual organ-dysfunction risk profiles influencing the outcome. METHODS: Fifty seven patients (53 men, 4 women, mean age 71.8 +/- 8.8 years) with ruptured abdominal aortic aneurysms underwent graft replacement in a three year period. Fourty eight preoperative, 13 intraoperative and 34 postoperative variables were analyzed. A multi-organ dysfunction (MOD) score was used. RESULTS: The perioperative mortality rate was 31%. Significance of pre-existing risk factors at admission was identified only for cardiovascular diseases. Multiple linear regression analysis indicated that hemoglobin < 90 g/l, systolic blood pressure < 80 mmHg and ECG signs of ischemia at admission are highly significant risk factors. Patients, who died later than 48 hours postoperatively, deceased mainly from MOD (93%) and required intensive care significantly longer than surviving patients (p < 0.0005). All patients with a MOD score > or = 4 died (n = 7). These patients required 26% of all ICU-days and 72% of the ICU-days of the nonsurvivors. CONCLUSION: Patients with ruptured aortic aneurysms should not be excluded from treatment. However, a physiological scoring system after 48 h appears justifiable in order to decide on the appropriateness of continued ICU support.