Early and systematic administration of fibrinogen concentrate in postpartum haemorrhage following vaginal delivery: the FIDEL randomised controlled trial.

OBJECTIVE: To assess the benefits and safety of early human fibrinogen concentrate in postpartum haemorrhage (PPH) management. DESIGN: Multicentre, double-blind, randomised placebo-controlled trial. SETTING: 30 French hospitals. POPULATION: Patients with persistent PPH after vaginal delivery requiring a switch from oxytocin to prostaglandins. METHODS: Within 30 minutes after introduction of prostaglandins, patients received either 3 g fibrinogen concentrate or placebo. MAIN OUTCOME MEASURES: Failure as composite primary efficacy endpoint: at least 4 g/dl of haemoglobin decrease and/or transfusion of at least two units of packed red blood cells within 48 hours following investigational medicinal product administration. Secondary endpoints: PPH evolution, need for haemostatic procedures and maternal morbidity-mortality within 6 ± 2 weeks after delivery. RESULTS: 437 patients were included: 224 received FC and 213 placebo. At inclusion, blood loss (877 ± 346 ml) and plasma fibrinogen (4.1 ± 0.9 g/l) were similar in both groups (mean ± SD). Failure rates were 40.0% and 42.4% in the fibrinogen and placebo groups, respectively (odds ratio [OR] = 0.99) after adjustment for centre and baseline plasma fibrinogen; (95% CI 0.66-1.47; P = 0.96). No significant differences in secondary efficacy outcomes were observed. The mean plasma FG was unchanged in the Fibrinogen group and decreased by 0.56 g/l in the placebo group. No thromboembolic or other relevant adverse effects were reported in the Fibrinogen group versus two in the placebo group. CONCLUSIONS: As previous placebo-controlled studies findings, early and systematic administration of 3 g fibrinogen concentrate did not reduce blood loss, transfusion needs or postpartum anaemia, but did prevent plasma fibrinogen decrease without any subsequent thromboembolic events. TWEETABLE ABSTRACT: Early systematic blind 3 g fibrinogen infusion in PPH did not reduce anaemia or transfusion rate, reduced hypofibrinogenaemia and was safe.

Comparison of scores associating symptoms and rescue medication use for evaluating the efficacy of allergy immunotherapy in seasonal allergic rhinoconjunctivitis: results from five trials.

BACKGROUND: Over the past decade, regulatory bodies and scientific societies recommended, as primary efficacy outcome, a score that reflects both symptom severity and use of rescue medication for clinical trials in allergy immunotherapy (AIT). OBJECTIVE: We sought to compare the results obtained with two subject-specific scores, the Combined Score (CS) and the Adjusted Symptom Score (AdSS), for assessment of AIT in seasonal allergic rhinoconjunctivitis due to birch and grass pollen allergens. METHODS: CS and AdSS were evaluated in subjects receiving a 300IR dose of allergen extract daily, by sublingual route, in four clinical trials with the 5-grass pollen tablet (NCT00367640, NCT00409409, NCT00955825 and NCT00418379) and one with the birch pollen solution (NCT01731249). The CS is derived from the Rhinoconjunctivitis Total Symptom Score (RTSS) and the Rescue Medication Score (RMS) giving equal weight to symptoms and medication use. The AdSS is a symptom score adjusting for rescue medication use. Efficacy end-points were analysed using an analysis of covariance linear model. RESULTS: In all trials, despite the different constructs of the two scores, Combined Score or Adjusted Symptom Score were similarly reduced in the 300IR group compared to the placebo group. Treatment effect was consistently demonstrated with both scores, CS and AdSS, used as either daily scores or average of the daily scores over the pollen season. Minor differences with the same statistical conclusions were observed between the results, leading to the same interpretation. CONCLUSIONS AND CLINICAL RELEVANCE: The two scores, combined and adjusted scores, for evaluation of clinical efficacy of AIT have led to similar results, with similar statistical conclusions and similar interpretation.

Analysis of an incomplete binary outcome derived from frequently recorded longitudinal continuous data: application to daily pain evaluation.

Randomized clinical trials increasingly collect daily data, frequently using electronic diaries. Such data are usually summarized into an 'intermediate' continuous outcome (such as the mean of the daily values in a period before a scheduled clinic visit). These are in turn often summarized further into a binary outcome, for example, indicating whether the intermediate continuous outcome has improved by a prespecified amount from randomization. This article compares and contrasts statistical approaches for analyzing such binary outcomes when the underlying study is subject to dropout so that some of the underlying diary data are missing. Such analysis involves rigorous rules for the derivation of outcomes, a thorough data exploration for the selection of covariates, and an elucidation of the missingness mechanism. The investigated statistical methods for treatment-effect analysis are based on direct modeling and on multiple imputation and are applied either to the binary outcome or the intermediate continuous outcome or to the daily diary data. These are compared on the basis of criteria for inferences at prespecified times during the follow-up. We show that multiple-imputation methods are particularly well adapted to our context and that missing data imputation on the daily diary data, rather than the derived outcomes, makes best use of the available information. The data set, which motivated our investigation, comes from a placebo-controlled clinical trial to assess the effect on pain of a new compound.

The average Adjusted Symptom Score, a new primary efficacy end-point for specific allergen immunotherapy trials.

BACKGROUND: In clinical trials, the efficacy of immunotherapy for allergic rhinoconjunctivitis symptoms is often evaluated with the average Rhinoconjunctivitis Total Symptom Score (ARTSS). Effective treatment is associated with a lower ARTSS vs. placebo but use of rescue medication to alleviate symptoms reduces the RTSS and decreases the mean difference between active treatment and placebo groups. OBJECTIVE: To develop and describe the average Adjusted Symptom Score (AdSS), a new end-point reflecting symptom severity and rescue medication use in allergic rhinoconjunctivitis trials. METHODS: To calculate the AdSS, the RTSS is adjusted as follows: if a patient takes rescue medication on day d, the day's AdSS (AdSS(d)) is defined as the value of RTSS(d) or AdSS(d-1), whichever is higher. The AdSS on the following day (AdSS(d+1)) is defined as the value of RTSS(d+1) or AdSS(d), whichever is higher. The average of the daily AdSSs (during the season) was calculated post hoc for two trials investigating the efficacy of five-grass pollen sublingual immunotherapy tablets in adult and paediatric patients and compared with the ARTSS and three other outcome measures (the average Rescue Medication Score (ARMS), the ARTSS and the average Combined Score). RESULTS: The average AdSS clearly discriminated between active and placebo treatments and confirmed the original ARTSS results. Adjustment for rescue medication use decreased the observed placebo effect. CONCLUSION AND CLINICAL RELEVANCE: The average AdSS can be a valuable alternative to the ARTSS as a primary efficacy end-point in grass pollen allergic rhinoconjunctivitis trials. By adjusting the RTSS for rescue medication use, the AdSS can estimate symptom severity and the treatment effect more accurately. The AdSS is now being tested prospectively in large clinical trials.

Clinical and biological efficacy of preservative-free NAAGA eye-drops versus levocabastine eye-drops in vernal keratoconjunctivitis patients.

AIMS: This comparative and randomised pilot study assessed the clinical and biological efficacy of Naaxia Sine(R) eye-drops versus levocabastine eye-drops in the treatment of vernal keratoconjunctivitis (VKC). METHODS: Twenty-three VKC patients were randomised and treated bilaterally for 28 days with N-acetyl-aspartyl-glutamate (NAAGA) or levocabastine (LEVO) eye-drops. The primary efficacy variable, overall evolution of eosinophil cationic protein (ECP) tear concentrations, was assessed in a masked fashion on D0, D7 and D28. Clinical symptoms and signs were reported at the same time points. Biological parameters were analysed with a non-parametric rank-based approach. Global tolerance was assessed by the investigator and patient. RESULTS: At all time points, ECP tear levels were significantly reduced in the NAAGA compared with the LEVO group (p = 0.023). Reduction of eosinophil leucocytes and tear lymphocytes was higher not significant in the NAAGA group. The same trend was observed for the evolution of total ocular symptom score. There were no significant differences between treatment groups in the occurrence of adverse effects, except for burning which was more frequent in the LEVO group (p = 0.002). CONCLUSION: The anti-eosinophilic actions of NAAGA were shown by a significant reduction of ECP tear concentrations. A decreased lymphocyte count and an overall improvement of the symptomatology were also noted. Moreover, the tolerability of NAAGA appeared to be better.

Efficacy of fusafungine in acute rhinopharyngitis: a pooled analysis.

Upper respiratory tract infections are generally mild but they are associated with an enormous loss in productivity. Treatment consists of reduction of local symptoms e.g. local inflammation and prevention of potential superinfections. Besides its bacteriostatic activity against most micro-organisms involved in respiratory tract infections fusafungine displays original anti-inflammatory properties. To optimise nasal and throat deposition, a new fusafungine oro-nasal spray using HFA 134a was developed and its efficacy was evaluated in patients with acute rhinopharyngitis based on improvement of significant nasal symptoms. Three randomised double-blind placebo-controlled parallel-group studies with identical objectives design and dosage were performed and results were pooled for a better evaluation of treatment effect (532 patients). The percentage of responders (patients with nasal symptom score improvement from Day 0 to Day 4) was 61.5 +/- 2.9% with fusafungine vs 46.8 +/- 3.1% with placebo (p=0.009) with an odds ratio of 1.8 (p=0.01) in favour of fusafungine. The nasal symptom score distribution at Day 4 showed an odds ratio of 1.56 (p=0.011) also in favour of fusafungine. For patients treated early (onset of symptoms 1 pounds day) the percentage of responders was 65.9 +/- 4.1% with fusafungine vs 38.3 +/- 4.0% with placebo (p=0.022) with an odds ratio of 3.08 (p=0.033) in favour of fusafungine. Therefore fusafungine through its dual bacteriostatic and original anti-inflammatory properties is an effective treatment of acute rhinopharyngitis especially when administered early.

IgG subclass distribution in serum and various mucosal fluids of HIV type 1-infected subjects.

We measured total IgG1, IgG2, IgG3, and IgG4 concentrations by ELISA in serum (S), total saliva (TS), cervicovaginal secretions (CVS), seminal secretions (SPE), and rectal secretions (RS) from either CDC II/III HIV-1-infected subjects or healthy volunteers. Human serum albumin was measured in parallel to calculate the relative coefficient of excretion (RCE). Levels of IgG1 and IgG3 directed against gp120 MN also were measured by ELISA in all samples, and the specific activity (SA) calculated. HIV-1-specific IgG2 and IgG4 were not compared, as total IgG2 and total IgG4 levels in HIV-1-infected subjects were found to be lower than in the healthy controls. Despite substantial interindividual variability, total IgG1 and IgG3 concentrations in all fluids were greater in the HIV-1-infected subjects than in the healthy controls. Calculations of RCE indicated predominantly a transudative origin for IgG subclasses in the different mucosal fluids, except for CVS, in which IgG1, IgG2, and IgG4 was produced locally. The transduction behavior of IgG3 in secretions appears to be different from that of other IgG subclasses. HIV-1-infected subjects were considered positive for IgG1 and IgG3 antibodies against gp120 MN if their antibody levels exceeded the maximum titer measured in the control group. Positive levels of anti-gp120 MN IgG1 were detected for 100% of HIV-1-infected individuals in S, CVS, and SPE, 97% in TS, and 75% in RS. Fewer subjects had positive levels of IgG3 to gp120 MN in their secretions (maximum 67% in CVS). Despite the low concentrations of total IgG3, mean SA values for IgG3 to gp120 MN were greater in secretions than in serum. No significant difference in the SA values for IgG1 to gp120 MN was observed between the different fluids. Only CVS had a local production of HIV-specific IgG1 Our results highlight the importance of an HIV-specific IgG1 and IgG3 immune response in mucosal fluids from HIV-1-infected subjects.

Comparison of the distribution of IgG and IgA antibodies in serum and various mucosal fluids of HIV type 1-infected subjects.

We compared IgG and IgA distribution in serum, three different salivary samples, two different rectal secretion samples, cervicovaginal secretions, and seminal secretions from asymptomatic CDC stage II/III HIV-1-infected subjects (n = 44) and from HIV-1-seronegative volunteers (n = 52). In-house ELISAs were used to measure total IgG and total IgA levels, as well as HIV-specific anti-gp120 MN and anti-p24 LAI IgG and IgA. Human serum albumin was titrated in parallel to calculate the relative coefficient of excretion (RCE). In spite of substantial interindividual variability, total IgG concentrations in all fluids were found to be significantly greater in the HIV-1-infected group than in the seronegative subjects. Calculation of RCE values revealed three different types of mucosal secretion: secretions with no local Ig production, such as sperm; secretions with local production of IgA and transudative origin of IgG, such as salivary and rectal samples; and secretions with local production of both IgG and IgA, such as in cervicovaginal secretions. For all mucosal specimens from HIV-1-infected subjects, the response to HIV-1 was predominantly IgG, with highest titers observed in cervicovaginal secretions (although these were lower than serum levels). In contrast, the specific IgA response appeared weaker in the mucosa than in serum.

Development and standardization of methods to evaluate the antibody response to an HIV-1 candidate vaccine in secretions and sera of seronegative vaccine recipients.

Enzyme-linked immunosorbent assays (ELISA) were developed to test, in serum and mucosal samples, total IgG, total IgA, serum albumin, and anti-gp120 MN and anti-p24 LAI IgG and IgA levels. These ELISAs were optimized according to reagents and experimental conditions. Inter- and intra-assay coefficients of variation ranged from 3.3% to 18.6%. The ELISA results were linear and precise, and for anti-HIV-1 IgG and IgA, the analytical recovery was close to 100%. For IgG and IgA titration against gp120 MN and p24 LAI, standards were made using pooled sera or gammaglobulins with assigned titres in ELISA units per ml (EU/ml). These standards were used to obtain a linear regression curve that could then be used to obtain the titres of experimental samples. The cut-offs for positivity were determined for sera and mucosal fluid using healthy controls. Validation conditions were defined for ELISAs, and samples that did not satisfy these conditions were retested. Measurement of total IgG and IgA allowed normalization and comparison of the results of specific immunoglobulin levels between different samples. Serum albumin was tested as a marker of transudation from serum to mucosal fluid, allowing calculation of the relative coefficient of excretion, which is one element required to determine the origin of the immunoglobulin detected in mucosal samples. These ELISAs were developed with samples from HIV-1-infected and healthy subjects. We now have the tools to study and understand mucosal immunity in seronegative subjects vaccinated with an HIV-1 candidate vaccine.

Symptomatic efficacy of avocado/soybean unsaponifiables in the treatment of osteoarthritis of the knee and hip: a prospective, randomized, double-blind, placebo-controlled, multicenter clinical trial with a six-month treatment period and a two-month followup demonstrating a persistent effect.

OBJECTIVE: To assess the efficacy and safety of avocado/soybean unsaponifiables (ASU) in the treatment of patients with symptomatic osteoarthritis (OA) of the knee or hip, as well as the potential residual effects of ASU after stopping treatment, to determine whether ASU might be a symptomatic slow-acting drug for the treatment of OA. METHODS: One hundred sixty-four patients with regular, painful, primary OA of the knee (n = 114) or hip (n = 50) entered a prospective, randomized, double-blind, placebo-controlled, parallel-group, multicenter trial with a 6-month treatment period and a 2-month posttreatment followup. A 15-day washout period for nonsteroidal antiinflammatory drugs (NSAIDs) preceded the study. Efficacy was judged according to 1) Lequesne's functional index (LFI) and 2) pain on Huskisson's visual analog scale (VAS; 100-mm scale), intake of NSAIDs/analgesics, and overall disability score (by 100-mm VAS). RESULTS: Eighty-five patients received ASU; 79 received placebo. One hundred forty-four patients were evaluable at month 6 (75 taking ASU; 69 taking placebo). The mean +/- SEM LFI score decreased from 9.7 +/- 0.3 to 6.8 +/- 0.4 in the ASU group and from 9.4 +/- 0.3 to 8.9 +/- 0.4 in the placebo group (P < 0.001 for intergroup difference at month 6). Pain decreased from 56.1 +/- 1.6 mm to 35.3 +/- 2.3 in the ASU group and from 56.1 +/- 1.8 mm to 45.7 +/- 2.6 in the placebo group (P = 0.003 at month 6). NSAID consumption was slightly lower in the ASU group. Fewer patients in the ASU group required NSAIDs (48%, versus 63% in the placebo group; P = 0.054). The success rate was 39% in the ASU group and 18% in the placebo group. Overall functional disability was significantly reduced in the ASU group. Improvement appeared more marked in patients with hip OA. A residual effect was observed at month 8. Tolerance was good to excellent for most patients. CONCLUSION: ASU treatment showed significant symptomatic efficacy over placebo in the treatment of OA, acting from month 2 and showing a persistent effect after the end of treatment.

Validation of an algofunctional index for osteoarthritis of the hand.

Although hand osteoarthritis is common, it has been the focus of few therapeutic trials. In addition to the problems raised by clinical trials in osteoarthritis in general and to the difficulties due to the unforeseeable course of osteoarthritis of the trapezometacarpal and finger joints, the lack of a clinical tool for assessing pain and function over time is an additional obstacle. We propose an algofunctional index designed for evaluation and symptomatic follow-up of patients with digital osteoarthritis. The index is based on a physician-administered questionnaire on 10 daily activities involving the hands. The patient is asked to answer each item using a 4-point verbal scale, from "possible without difficulty" (0) to "impossible" (3 points); thus, total scores range from 0 to 30. This index has been used in a few clinical placebo-controlled trials and was found sensitive to change. The aim of this study was to assess the metrological qualities of this index, including consistency (internal and external), sensitivity and specificity (by scoring the index in different groups of subjects), intra-observer reproducibility, and ease of use. Three hundred patients were recruited by 25 rheumatologists: 100 had a painful attack of digital and/or trapezometacarpal osteoarthritis (mean age: 64.9 years) with a score of more than 40 mm on a visual analog scale for overall pain severity (mean: 57.3 +/- 14 mm), 100 had "inactive" hand osteoarthritis (mean age 67.0 years), and 100 had no diseases of the upper limbs. Specificity/sensitivity: the mean index score was 12.41 +/- 5.41 in patients with painful OA, 4.28 +/- 3.87 in "inactive" cases, and 0.59 +/- 1.23 in controls. External consistency: the overall mean score was well correlated with pain severity: r = 0.49 (p < 0.001). Internal consistency: principal component analysis identified a primary axis responsible for 44.2% of the variance and two secondary axes each responsible for slightly more than 9% of the variance. None of the questions seemed redundant. Intra-observer reproducibility: two evaluations done one hour apart in symptomatic patients yielded the following scores: 12.32 +/- 5.41 and 12.5 +/- 5.51 (correlation: 0.95; mean difference: 0.17 +/- 1.64; coefficient of variation: 9.32%). Kappa values for both measurements of each item ranged from 0.68 to 0.87. Ease of use: mean time needed to determine the score 2.5 +/- 2 min. The scoring process was considered simple by 100% of investigators and easy/very easy by 98% of patients.(ABSTRACT TRUNCATED AT 400 WORDS)

Bayesian predictive approach for inference about proportions.

This paper investigates the Bayesian procedures for comparing proportions. These procedures are especially suitable for accepting (or rejecting) the equivalence of two population proportions. Furthermore the Bayesian predictive probabilities provide a natural and flexible tool in monitoring trials, especially for choosing a sample size and for conducting interim analyses. These methods are illustrated with two examples where antithrombotic treatments are administrated to prevent further occurrences of thromboses.