AURIEL-PsO: a randomized, double-blind phase III equivalence trial to demonstrate the clinical similarity of the proposed biosimilar MSB11022 to reference adalimumab in patients with moderate-to-severe chronic plaque-type psoriasis.

BACKGROUND: MSB11022 is a proposed adalimumab biosimilar. OBJECTIVES: To compare the efficacy, safety and immunogenicity of MSB11022 with reference adalimumab. METHODS: AURIEL-PsO was a double-blind randomized controlled equivalence trial, in which patients with moderate-to-severe chronic plaque-type psoriasis were randomized 1 : 1 to MSB11022 or reference adalimumab. The primary end point was ≥ 75% improvement in Psoriasis Area and Severity Index (PASI 75) at week 16, with a prespecified equivalence interval of ± 18%. Patients with a ≥50% improvement in PASI at week 16 were eligible to enter a double-blind extension period: patients receiving MSB11022 continued treatment, and patients receiving reference adalimumab were rerandomized 1 : 1 either to continue reference adalimumab or to switch to MSB11022. Other efficacy end points and safety, immunogenicity and pharmacokinetic parameters were evaluated at scheduled visits up to weeks 52 (efficacy and immunogenicity), 54 and 66 (safety). RESULTS: In total, 443 patients were randomized. The difference in PASI 75 response rates at week 16 between the treatment arms was -1·9%, and the 95% confidence interval (-7·8% to 4·1%) was within the prespecified equivalence interval. No notable difference in the incidence of treatment-emergent adverse events was observed between treatment arms up to the end of the trial, and no new safety signals were observed. Following treatment switch at week 16, no clinically meaningful differences in safety or immunogenicity were seen between treatment arms through to the end of the observation period. CONCLUSIONS: Therapeutic equivalence between MSB11022 and reference adalimumab was demonstrated. AURIEL-PsO provides evidence to support the similarity of both products with regard to efficacy, safety and immunogenicity. What's already known about this topic? Adalimumab is a fully human antitumour necrosis factor-α monoclonal antibody, indicated for the treatment of multiple inflammatory disorders, including psoriasis, psoriatic arthritis, rheumatoid arthritis, inflammatory bowel diseases and ankylosing spondylitis. MSB11022 is a proposed adalimumab biosimilar that has shown structural and functional similarity to the reference product in an extensive analytical comparability exercise. MSB11022 has demonstrated bioequivalence and comparable safety and immunogenicity profiles in a phase I study in healthy volunteers. What does this study add? This phase III study confirmed equivalent efficacy for MSB11022 and reference adalimumab in patients without any immunomodulation comedication in moderate-to-severe chronic plaque-type psoriasis at week 16. The efficacy, safety and immunogenicity of MSB11022 and reference adalimumab were similar over the respective observation periods (week 52 for efficacy and immunogenicity, week 66 for safety). A switch from reference adalimumab to MSB11022 at week 16 did not impact efficacy, safety or immunogenicity.

Correction to: Recommendations for the Development and Validation of Neutralizing Antibody Assays in Support of Biosimilar Assessment.

In the published article, the author B. Babbitt was cited as affiliation 9, but should have been cited as affiliation 2. In addition, there are 2 errors in the affiliations. The correct affiliations are shown in this erratum.

Recommendations for the Development and Validation of Neutralizing Antibody Assays in Support of Biosimilar Assessment.

The American Association of Pharmaceutical Scientists (AAPS) biosimilar focus group on nonclinical and clinical assays has developed this manuscript to guide the industry on best practices and testing strategies when developing neutralizing antibody (NAb) assays for biosimilar programs. The immunogenicity assessment to biosimilar and originator drug products is one of the key aspects of clinical programs for biosimilars to demonstrate biosimilarity. Establishing that there are no clinically meaningful differences in immune response between a proposed product and the originator product is a key element in the demonstration of biosimilarity. It is critical to collect, evaluate, and compare the safety and immunogenicity data from the clinical pharmacology, safety, and/or efficacy studies especially when the originator drug product is known to have potential for immune-mediated toxicity. This manuscript aims to provide a comprehensive review and recommendations on assay formats, critical reagents, approaches to method development, and validation of the neutralizing antibody assays in extrapolation within the scope of biosimilar drug development programs. Even if there are multiple options on the development and validation of NAb assays for biosimilar programs, the type of drug and its MoA will help determine the assay format and technical platform for NAb assessment (e.g., cell-based or non-cell-based assay). We recommend to always perform a one-assay approach as it is better to confirm the biosimilarity using one-assay for NAb. If a one-assay approach is not feasible, then a two-assay format may be used. This manuscript will provide all the details necessary to develop NAb assays for biosimilars.

High bone-binding capacity of ibandronate in hemodialysis patients.

Bisphosphonates are a potential therapy for osteoclast-mediated bone disease, such as renal osteodystrophy. This study evaluated ibandronate bone-binding in patients with secondary hyperparathyroidism and renal osteodystrophy and examined whether there is a correlation with bone metabolism parameters. Sixteen patients with end-stage renal disease and secondary hyperparathyroidism receiving regular hemodialysis were recruited to this 12-week trial. Intravenous ibandronate 2 mg was administered for 5 min every 4 weeks directly after hemodialysis. Ibandronate levels were measured 15 min after infusion and at trough levels before the next hemodialysis. Serological markers of bone metabolism were also measured. After the first infusion, the peak ibandronate level was 154 +/- 75.1 ng/ml and the trough level was 2.7 +/- 1.7 ng/ml. At week 12, peak and trough ibandronate levels were 164.8 +/- 89.9 ng/ml and 3.2 +/- 2.6 ng/ml, respectively. Ibandronate bone uptake was 98.0% at first application and 98.4% at week 12. In patients with remaining diuresis, ibandronate urine excretion was < 0.001% of the administered dose. There was no correlation of ibandronate bone-binding with parameters of osteoclast activity or parathyroid hormone (PTH). The correlation with markers of osteoblast activity was significant but weak. Ibandronate had a bone-binding capacity of approximately 98% in hemodialysis patients. After repeated dosing ibandronate bone-uptake remained stable and was independent of osteoclast activity or PTH levels. Due to the high bone-binding of ibandronate in these patients, a 2 mg dose of intravenous ibandronate is equivalent to a 4-5 mg dose of ibandronate in patients with normal renal function.

[Evaluation of two commercial enzyme immunoassays for diagnosis of hepatitis C in the conditions of a virology laboratory]. / Evaluation de deux trousses commerciales EIA pour le diagnostic de l'hépatite C dans les conditions d'un laboratoire de virologie.

BACKGROUND: Most studies which evaluate antibody detection assays are conducted on blood donors specimens, i.e healthy individuals. Sera collected in patients, vs healthy individuals, can make serological tests difficult because of possible non specific reactions interfering with serological tests. The aim of this work was to compare the specificity and the sensitivity of two commercial automated assays for the detection of hepatitis C virus antibody, Monolisa anti-HCV Plus on the Evolis automate (Biorad) and Axsym anti-HCV 3.0 (Abbott). PATIENTS AND METHOD: The prospective study of specificity included 2020 routine serum samples sent to our virology laboratory. The sensitivity was established with eight commercially available HCV seroconversion panels. RESULTS: The Monolisa and the Axsym assays showed a specificity of 99.64 and 99.12%, respectively. Of 49 specimens from eight commercially available HCV seroconversion panels, the number of positive results was 21 and 24 for the two tests, respectively. CONCLUSION: A statistical analysis of specificity and sensitivity results proved no significant difference between the two tests. Nevertheless, the Monolisa kits could be preferred for its more homogeneous sensitivity than the Axsym test and for its apparent better specificity. The final choice of a kit should also take into account the easiness to perform and an optimal integration in the usual practice of the concerned laboratory.

[Immunoblot in the serological diagnosis of hepatitis C virus infection]. / Intérêt de l'immunoblot dans l'évaluation du statut sérologique vis-à-vis de l'hépatite C.

The objective of the study was to assess three immunoblot assays, the Deciscan HCV Plus, the Riba and the Inno-Lia, on 44 discordant samples with three EIA kits. These immunoblots were considered as confirmation reagents. A result was considered as a false positive by anti-HCV antibody assay if the three immunoblots were negative or if two immunoblots were negative with the third being indeterminate and a negative virological genomic diagnosis observed on all the samples. The result was positive if at least two immunoblots out of three were positive. Thus, 34 samples were considered as false positive and ten samples were excluded because it was impossible to conclude between true or false positive result. The 44 discordant results were never confirmed as positive by the use immunoblot or PCR. The three immunoblots were negative for half of the samples and two immunoblots and one indeterminate were observed for 77% of the samples. The false positive results by the Monolisa assay were more often found indeterminate with the Deciscan assay than with the other immunoblots. That was also checked for Vitros/Riba pair. One of the explanations could be the use of common antigens for the reagents from the same manufacturer. The Inno-Lia test is the most specific immunoblot according to the results obtained in our study.

Long-term results after repair of truncus arteriosus communis in neonates and infants.

BACKGROUND: We reviewed our experience of truncus arteriosus communis (TAC) repair. METHODS: Between 05/90 and 10/01, 16 patients underwent complete repair of TAC (primary repair: group I, 12 patients, secondary repair: group II, 4 patients). Age was 2.4 months [5 days-8.8 months] (median [range]) in group I, and 8.3 [5.6-13.5] years in group II. Continuity from the right ventricle to the pulmonary artery was achieved using a valved conduit. All patients had regular follow-up examinations. RESULTS: There was one early death in each group (12.5%). Follow-up was 9 [1.2-12.7] years. Valved conduit failure occurred in 8 patients (67 %) in group I (group II, 1 patient, 33 %) requiring replacement at 2.5 [0.3-4.3] years (group II, 5.8 years). Severe neo-aortic valve regurgitation after truncal valve repair was observed in one patient, requiring valve replacement at 8.5 years in association with repeat homograft replacement (group I). Actual echocardiographic examination revealed normal ventricular function. Moderate conduit dysfunction was noted in 2 patients (group I). CONCLUSIONS: Complete repair of truncus arteriosus communis can be performed with excellent long-term results.

The index of pulmonary vascular disease in children with congenital heart disease: relationship to clinical and haemodynamic findings.

OBJECTIVE: We asked whether a scoring system [index of pulmonary vascular disease (IPVD)] that quantifies the individual pulmonary vascular pathology would relate to postoperative survival in patients with congenital heart disease and pulmonary hypertension (PH). METHODS: Lung biopsy specimens from 28 patients at a median age of 6 months (1 month to 21 years) were analysed qualitatively and morphometrically. The IPVD and other morphometric parameters were related to haemodynamic findings and survival. RESULTS: Mean pulmonary artery pressure (PAP) was 44 mmHg (15-72 mmHg), and the resistance to pulmonary perfusion was 5 U x m(2) (0.9-14 U x m(2)). There were three early (in-hospital) and three late deaths during the follow-up period of 2.5 years (6 months to 7 years). Incipient plexiform lesions were observed in one infant with trisomy 21 and complete atrioventricular septal defect (cAVSD). An IPVD score above the upper critical limit (>2.2) was not observed during the first year of life. On discriminant analysis, morphometric parameters could not predict mortality ( P=0.08). CONCLUSIONS: The IPVD is not helpful to predict surgical mortality during the first year of life. Patients with trisomy 21 and cAVSD may show advanced pulmonary vascular disease in infancy.

A multivariate statistical analysis to follow the course of disease after infection of cats with different strains of the feline immunodeficiency virus (FIV).

A descriptive multivariate assay is described which is suitable to analyze results of a biological experiment with small sample size but high qualitative and quantitative complexity of variables. This type of assay allows evaluation of multiple variables observed in the course of an experimental virus infection (e.g. viremia, nucleic acid detection, antibody titers, clinical parameters, anti-microbial treatments or vaccination) in a single graph. In our study, a multiple correspondence analysis (MCA) was used to correlate a total of 145 measurements from each of a dozen of variables measured in five groups of three cats infected by five isolates of feline immunodeficiency virus (FIV). Three groups of virus isolates with distinct virulence were defined and correlation between dynamics of lymphocyte subset counts and viral virulence was established. Comparison between the primary stages of illness and follow-up examinations were of prognostic value and are thus helpful for development and monitoring of therapeutic strategies.

The urgent pulmonary embolectomy: mechanical resuscitation in the operating theatre determines the outcome.

BACKGROUND: The urgent pulmonary embolectomy as a surgical treatment of acute massive pulmonary embolism (PE) is still the subject of controversial discussion regarding indication, operative technique, and prognosis. METHODS: From 10/89 to 9/97 40 patients underwent urgent exploration of the pulmonary artery with the aid of extracorporeal circulation (ECC). RESULTS: The overall operative mortality was 35%. Univariate and multivariate logistic regression analysis showed preoperative hemodynamics and cardiopulmonary resuscitation (CPR) as the most important predictive factors for outcome: mortality rate was significantly higher after CPR (=63%) than without CPR (=10%) (p = 0.001). Other factors such as immobility, overweight, and concomitant cardiopulmonary disease also had an influence on the postoperative outcome. CONCLUSIONS: Pulmonary embolectomy (on the beating heart with ECC under total bypass) under stable hemodynamics, without CPR however, still constitutes an important form of treatment of acute massive PE with excellent long-term results.

Interactions of "Limax amoebae" and gram-negative bacteria: experimental studies and review of current problems.

Free-living amoebae can harbour bacteria inside their cysts giving them a microhabitat and protecting them from disinfectants. The aim of this study was to evaluate the potential importance of "Limax amoebae" as vectors for environmental and nosocomial bacteria in a hospital. It was shown that free-living amoebae are ubiquitous in the investigated hospital, occur syntopically with facultative human pathogens (Comamonas acidovorans and Pseudomonas aeruginosa) and may serve as hosts not only for these but also for bacteria isolated from clinical specimens (Escherichia coli, Proteus mirabilis and Pseudomonas aeruginosa); temperature is apparently of crucial importance for the interactions between these microorganisms. Recent studies have shown that "Limax amoebae" apart from acting as protective hosts, may also play a role for the thermotolerance, invasiveness and antibiotic-resistance of bacteria. Considering also the reduced immune-status of many patients, this "symbiosis" of free-living amoebae and bacteria might still be of underestimated hospital-hygienic importance.

Progesterone production by binucleate trophoblastic cells of cows.

Incubation of 1 x 10(6) bovine binucleate trophoblastic cells (BTC) for 6 h with 0.20 and 0.30 microM-Ca2+ ionophore A23187 increased (P less than 0.01) net progesterone production 49% and 111%, respectively, compared to BTC without A23187. Addition of 3 mM-8-bromo-cAMP with A23187 had no effect on the response. Trifluoperazine (40 microM), an inhibitor of calmodulin, and ethylene glycol-bis-(beta-aminoethyl ether)-N,N,N',N'-tetraacetic acid (1.0 mM), a Ca2+ chelator, decreased (P less than 0.01) progesterone production. Progesterone production by BTC incubated for 6 h with fetal bovine serum or lipoprotein-deficient serum (LPDS) did not differ. Addition of bovine serum low-density lipoprotein or high-density lipoprotein to LPDS did not affect progesterone production. Aminoglutethimide (100 microM) decreased (P less than 0.01) progesterone production by BTC. These results indicate that progesterone production by bovine BTC is Ca2+-dependent, cyclic nucleotide-independent, and not stimulated by bovine serum lipoproteins.

Insulin and glucose responses to glucose injection in fed and fasted obese and lean sheep.

Effects of short-term fasting on the insulin and glucose responses to injected glucose were determined in obese (n = 6) and lean (n = 6) Dorset ewes that were fed a maintenance level of energy intake. Sheep were assigned by Latin-square design to be fasted for 0 (fed), 12 or 24 h before glucose (350 mg/kg) was injected via jugular cannula at 2000 h with at least 7 d between successive tests. Insulin and glucose were quantified in jugular plasma samples. Pretreatment concentrations of insulin were affected (P less than 0.005) only by body condition with higher mean values in obese (23.5 +/- 3.3 microU/ml) than in lean (9.4 +/- 1.0 microU/ml) sheep. Pretreatment concentrations of glucose (53.6 +/- 1.8 mg/dl) were unaffected by body condition and fasting. The insulin responses to glucose, whether determined as absolute levels or response areas above base-line levels, were greater (P less than 0.005) in obese than in lean sheep regardless of fasting period. Insulin and glucose concentrations after glucose injection in lean sheep were unaffected by fasting. In contrast, the insulin response to glucose was greater (P less than 0.005) in fed obese than 12- or 24-h fasted obese sheep while glucose levels in the fed sheep were similar to those in the fasted obese sheep. Thus, factors associated with feeding enhanced the insulin response to glucose in obese sheep. In addition, obesity in sheep was associated with insulin resistance because basal hyperinsulinemia coexisted with euglycemia and because fractional removal rates of injected glucose were similar in obese and lean sheep despite much greater concentrations of insulin in obese sheep.

Progesterone and prostanoid production by bovine binucleate trophoblastic cells.

A procedure for preparing highly enriched suspensions of bovine binucleate trophoblastic cells was developed and data showing that these cells produce progesterone, prostacyclin (PGI2), and prostaglandin E2 (PGE2) were obtained. Approximately 200 X 10(6) enzymatically dissociated cells from bovine cotyledons were applied to the surface of a density gradient of 2% to 4% Ficoll-400 using the Wescor CELSEP sedimentation chamber. After 90-120 min of sedimentation at unit gravity, fractions containing binucleate trophoblastic cells were obtained and washed in HEPES-buffered Medium 199. Preparations of 90% to 100% binucleate trophoblastic cells were obtained routinely; viability was 50% to 80%. After incubation at 37 degrees C, concentrations (ng/10(5) cells) of progesterone were greater in those fractions containing binucleate cells than in those containing primarily smaller, mononucleate cells. Total progesterone secreted (mean +/- SEM) after 4 h by 1 X 10(5), 2 X 10(5), 4 X 10(5), 8 X 10(5), and 1.6 X 10(6) binucleate cells was 0.27 +/- 0.03, 1.01 +/- 0.09, 4.02 +/- 0.37, 10.31 +/- 0.92, and 20.96 +/- 2.23 ng, respectively (r = 0.997). Addition of 10% fetal bovine serum (FBS) or normal anestrous cow serum increased (P less than 0.05) production of progesterone by binucleate trophoblastic cells. Luteinizing hormone, follicle-stimulating hormone, prolactin, thyrotropin, and 8-bromo-adenosine 3',5'-cyclic monophosphate had no effect. Binucleate trophoblastic cells also produced PGI2 in relation to number of cells incubated (r = 0.996). Time courses for production of PGI2, PGE2, and progesterone were similar. Aspirin inhibited production of PGI2 and PGE2 by about 50% at a dose of 100 microM; FBS stimulated production of both prostanoids.

Influence of dietary cholesterol and fat on serum lipids in men.

The effect of changes in dietary cholesterol and fat on serum lipids was studied in 32 healthy men (mean age = 24.8 years). Subjects were fed a controlled diet for 10 days providing 42 to 45% of the total calories from fat, a P/S ratio of 0.3 to 0.5 and two eggs per day. During the next eight weeks, 16 subjects received each of the following diets for four weeks in a crossover design: 1) a control diet with two eggs per day or 2) the control diet with eggs replaced by a cholesterol-free egg substitute. The remaining 16 subjects received each of the following diets in a similar crossover design: 1) a modified-fat diet containing 35% of the total calories from fat, a P/S ratio greater than or equal to 1.0 and two eggs per day or 2) the same modified-fat diet with the egg substitute replacing the eggs. The two-week cycle of menus repeated throughout the study included a wide variety of foods commonly consumed in this country. Although the response of individual subjects varied, analysis of variance showed a significant decrease in serum total cholesterol related to replacement of eggs with the egg substitute and to modification in the type and amount of dietary fat. A significant diet-treatment interaction or sequencing effect was not found. Change in cholesterol intake related to addition or deletion of two eggs in the daily diet had no significant effect on serum triglycerides, high density lipoprotein cholesterol, or relative lipoprotein concentrations.

[Work capacity and multiple sclerosis]. / Arbeitsfàhigkeit und multiple sklerose.

A report is given on the working capacity of 431 patients suffering from multiple sclerosis (MS) who were treated as inpatients at the neurologic-psychiatric clinic of the Medical Academy of Dresden in the period from 1960 to 1977. Leaving out of account the age when the disease began, the course of the disease and the symptoms, 84 per cent of the patients still alive were still able to work after 1 to 5 years, 80.1 per cent after 6 to 10 years and 75 per cent after more than 21 years. Patients with cerebral symptoms and those with an intermittent course of the disease were best suited for an integration in the working process. The largest part of the patients who had to be declared invalid was found among the agricultural workers. In 18.6 per cent of the patients, declaration of invalidity could be avoided by an appropriate workplace.