A randomized controlled trial comparing the efficacy and safety of two HMG preparations gaining their LH bioactivity from different HCG sources.

In this prospective, controlled, randomized, multicentre, non-inferiority study, efficacy and safety of two HMG preparations (Menopur®- Ferring and Meriofert®- IBSA Institut Biochimique SA) for ovarian stimulation were compared (270 women undergoing IVF aged between 18 and 39 years; BMI 30 kg/m2 or less; less than three prior completed assisted reproduction technique cycles). A standard long down-regulation with gonadotrophin-releasing hormone agonist protocol, with HCG triggering was used; primary end-point was total number of oocytes retrieved; attention was paid toovarian hyperstimulation syndrome (OHSS). No statistically significant differences between the treatment groups were reported for most of the clinically significant end-points, including embryo quality, fertilization rate, implantation rate, ongoing pregnancy rate and live birth rate. Total number of oocytes retrieved was higher in the new HMG group compared with the reference (11.6 ± 6.6 and 9.7 ± 5.9, respectively, with a 95% CI of the difference equal +0.43 to +3.43). Increased number of oocytes was obtained through a shorter stimulation, but HMG units per oocyte retrieved were equivalent. The safety profile of the products for frequency of ovarian hyperstimulation syndrome was the same. This study showed that the new HMG preparation is a viable alternative for conducting ovarian stimulation in IVF cycles.

A randomized, open-label, multicenter study of the efficacy and safety of intravesical hyaluronic acid and chondroitin sulfate versus dimethyl sulfoxide in women with bladder pain syndrome/interstitial cystitis.

AIMS: Intravesical instillation of hyaluronic acid (HA) plus chondroitin sulfate (CS) in women with bladder pain syndrome/interstitial cystitis (BPS/IC) has shown promising results. This study compared the efficacy, safety, and costs of intravesical HA/CS (Ialuril® , IBSA) to dimethyl sulfoxide (DMSO). METHODS: Randomized, open-label, multicenter study involving 110 women with BPS/IC. The allocation ratio (HA/CS:DMSO) was 2:1. Thirteen weekly instillations of HA (1.6%)/CS (2.0%) or 50% DMSO were given. Patients were evaluated at 3 (end-of-treatment) and 6 months. Primary endpoint was reduction in pain intensity at 6 months by visual analogue scale (VAS) versus baseline. Secondary efficacy measurements were quality of life and economic analyses. RESULTS: A significant reduction in pain intensity was observed at 6 months in both treatment groups versus baseline (P < 0.0001) in the intention-to-treat population. Treatment with HA/CS resulted in a greater reduction in pain intensity at 6 months compared with DMSO for the per-protocol population (mean VAS reduction 44.77 ± 25.07 vs. 28.89 ± 31.14, respectively; P = 0.0186). There were no significant differences between treatment groups in secondary outcomes. At least one adverse event was reported in 14.86% and 30.56% of patients in the HA/CS and DMSO groups, respectively. There were significantly fewer treatment-related adverse events for HA/CS versus DMSO (1.35% vs. 22.22%; P = 0.001). Considering direct healthcare costs, the incremental cost-effectiveness ratio of HA/CS versus DMSO fell between 3735€/quality-adjusted life years (QALY) and 8003€/QALY. CONCLUSIONS: Treatment with HA/CS appears to be as effective as DMSO with a potentially more favorable safety profile. Both treatments increased health-related quality of life, while HA/CS showed a more acceptable cost-effectiveness profile.

A randomized, controlled trial comparing the efficacy and safety of aqueous subcutaneous progesterone with vaginal progesterone for luteal phase support of in vitro fertilization.

STUDY QUESTION: Is the ongoing pregnancy rate with a new aqueous formulation of subcutaneous progesterone (Prolutex(®)) non-inferior to vaginal progesterone (Endometrin(®)) when used for luteal phase support of in vitro fertilization? SUMMARY ANSWER: In the per-protocol (PP) population, the ongoing pregnancy rates per oocyte retrieval at 12 weeks of gestation were comparable between Prolutex and Endometrin (41.6 versus 44.4%), with a difference between groups of -2.8% (95% confidence interval (CI) -9.7, 4.2), consistent with the non-inferiority of subcutaneous progesterone for luteal phase support. WHAT IS KNOWN ALREADY: Luteal phase support has been clearly demonstrated to improve pregnancy rates in women undergoing in vitro fertilization (IVF). Because of the increased risk of ovarian hyperstimulation syndrome associated with the use of hCG, progesterone has become the treatment of choice for luteal phase support. STUDY DESIGN, SIZE, DURATION: This prospective, open-label, randomized, controlled, parallel-group, multicentre, two-arm, non-inferiority study was performed at eight fertility clinics. A total of 800 women, aged 18-42 years, with a BMI of ≤ 30 kg/m(2), with <3 prior completed assisted reproductive technology (ART) cycles, exhibiting baseline (Days 2-3) FSH of ≤ 15 IU/L and undergoing IVF at 8 centres (seven private, one academic) in the USA, were enrolled from January 2009 through June 2011. PARTICIPANTS/MATERIALS, SETTING, METHODS: In total, 800 women undergoing IVF were randomized after retrieval of at least three oocytes to an aqueous preparation of progesterone administered subcutaneously (25 mg daily) or vaginal progesterone (100 mg bid daily). Randomization was performed to enrol 100 patients at each site using a randomization list that was generated with Statistical Analysis Software (SAS(®)). If a viable pregnancy occurred, progesterone treatment was continued up to 12 weeks of gestation. MAIN RESULTS AND THE ROLE OF CHANCE: Using a PP analysis, which included all patients who received an embryo transfer (Prolutex = 392; Endometrin = 390), the ongoing pregnancy rate per retrieval for subcutaneous versus vaginal progesterone was 41.6 versus 44.4%, with a difference between groups of -2.8% (95% CI -9.7, 4.2), consistent with the non-inferiority of subcutaneous progesterone for luteal phase support. In addition, rates of initial positive ß-hCG (56.4% subcutaneous versus 59.0% vaginal; 95% CI -9.5, 4.3), clinical intrauterine pregnancy with fetal cardiac activity (42.6 versus 46.4%; 95% CI -10.8, 3.2), implantation defined as number of gestational sacs divided by number of embryos transferred (33.2 versus 35.1%; 95% CI -7.6, 4.0), live birth (41.1 versus 43.1%; 95% CI -8.9, 4.9) and take-home baby (41.1 versus 42.6%; 95% CI -8.4, 5.4) were comparable. Both formulations were well-tolerated, with no difference in serious adverse events. Analysis with the intention-to-treat population also demonstrated no difference for any outcomes between the treatment groups. LIMITATIONS, REASONS FOR CAUTION: The conclusions are limited to the progesterone dosing regimen studied and duration of treatment for the patient population examined in this study. WIDER IMPLICATIONS OF THE FINDINGS: Subcutaneous progesterone represents a novel option for luteal phase support in women undergoing IVF who for personal reasons prefer not to use a vaginal preparation or who wish to avoid the side effects of vaginal or i.m. routes of administration. STUDY FUNDING/COMPETING INTERESTS: The study was funded by Institut Biochimique SA (IBSA). CAJ, BC, ST and CJ are employees of IBSA. FH currently consults for IBSA. TRIAL REGISTRATION NUMBER: NCT00828191.

Alzheimer special care units compared with traditional nursing home for dementia care: are there differences at admission and in clinical outcomes?

BACKGROUND: Studies comparing Alzheimer Special Care Units (ASCUs) with traditional nursing homes (NHs) have reported conflicting results. OBJECTIVES: To compare the characteristics and the effects on mortality, hospitalization, use of physical restraints, falls, and antipsychotics among patients admitted to ASCUs or to NHs. METHODS: A sequential cohort of patients with dementia was recruited and followed for 18 months in a sample of randomly selected ASCUs and NHs. Data on socio-demographic, cognitive, functional, behavioral, and clinical characteristics, and drug exposure were collected at baseline and at 6-month intervals up to 18 months. RESULTS: A total of 349 patients were enrolled in 35 ASCUs and 81 in 9 NHs. Patients admitted to ASCUs were younger, cognitively and functionally less impaired, but had more behavioral disturbances than those in NH. During follow-up, ASCU patients had a lower risk of hospitalization (odds ratio: 0.67; 95% confidence interval: 0.46-0.99; P=0.04), and use of physical restraints (odds ratio: 0.66; 95% confidence interval: 0.51-0.86; P=0.003), and showed a higher rate of withdrawal of antipsychotics (P=0.003). No difference was found in mortality and falls. Propensity score analysis gives similar results. CONCLUSIONS: This study found that patients with dementia in ASCUs had different baseline clinical and functional characteristics from those in NHs. They had a lower rate of hospitalization and use of physical restraints at 6-month follow-up, and a higher probability of having antipsychotic agents withdrawn.

Endometrial thickness on the day of embryo transfer is a poor predictor of IVF treatment outcome.

STUDY QUESTION: What is the independent contribution of endometrial thickness (EMT) on day of embryo transfer to achieving an ongoing pregnancy and live birth after IVF treatment? SUMMARY ANSWER: EMT is a poor predictor of IVF success and has only little independent prognostic value. WHAT IS KNOWN ALREADY: In a number of previous studies, pregnancy rates have been found to be lower in patients with thin endometrium. STUDY DESIGN SIZE DUARATION: This is a retrospective analysis of data from two large, randomized phase III studies (conducted in Europe and the USA) comparing s.c. progesterone with vaginal progesterone for luteal phase support. The studies were very similar in design, patient population and outcome, and the study data were combined and analysed on an individual patient level. PARTICIPANTS/MATERIALS SETTING METHOD: Subjects were infertile patients with an indication for IVF/ICSI, aged between 18 and 42 years, BMI <30 kg/m2, <3 prior ART cycles and ≥ 3 oocytes after controlled ovarian stimulation with GnRH-agonist or GnRH-antagonist. EMT was assessed on day of embryo transfer (n = 1401). The association of EMT and ongoing pregnancy rate was determined by comparison of outcomes by quantiles of EMT. The predictive capacity of EMT for ongoing pregnancy achievement was assessed at each millimeter cut-off. Finally, a regression model was built to determine the contribution of EMT among other confounders, such as age and oocyte numbers, on the likelihood of ongoing pregnancy and live birth. MAIN RESULTS AND THE ROLE OF CHANCE: In univariate analysis, ongoing pregnancy rates correlate to EMT. In patients above a cut-off of ≥9 mm EMT, the chance of pregnancy was higher as compared to patients with an EMT of 3-8 mm (odds ratio (OR) = 1.69, 95% CI: 1.23-2.35, P = 0.001; sensitivity 88.89%, specificity 17.52%, positive predictive value 39.02%, negative predictive value 72.64% and likelihood ratio 1.08). In multivariate regression analysis, after controlling for trial, female age and oocyte numbers, EMT was a statistically significant predictor of live birth (OR = 1.05, 95% CI: 1.00-1.10; P = 0.0351). If EMT indeed is an independent factor affecting outcome, this finding implies that at a baseline live birth rate of 20% an increase of 2 mm in EMT should result in an increase of the live birth rate of ~1.6%. LIMITATIONS REASONS FOR CAUTION: The independent contribution of EMT to live birth likelihood is small and may result from (undetermined) confounding. The EMT on day of embryo transfer is usually higher as compared to the EMT on day of triggering final oocyte maturation when it is conventionally assessed during routine cycle monitoring. Furthermore, endometrial lining pattern and/or subendometrial Doppler flow have not been assessed and, accordingly, the conclusions of this work are limited to only the thickness of the endometrium. WIDER IMPLICATIONS OF THE FINDINGS: EMT can be ignored during cycle monitoring of the majority of IVF patients and only the extremes of EMT deserve further diagnostic work-up. STUDY FUNDING/COMPETING INTERESTS: The study was supported by IBSA. G.G. has received personal fees and non-financial support from MSD, Ferring, Merck-Serono, Finox, TEVA, IBSA, Glycotope, Abbott, Gedeon-Richter as well as personal fees from VitroLife, NMC Healthcare, ReprodWissen, BioSilu and ZIVA. S.T. and B.C. are employees of IBSA. TRIAL REGISTRATION NUMBER: NCT00827983 and NCT00828191 (clinicaltrials.gov). TRIAL REGISTRATION DATE: 23 January 2009 (NCT00827983 and NCT00828191). DATE OF FIRST PATIENT'S ENROLMENT: January 2009 (NCT00827983 and NCT00828191).

Improved detection of differentially expressed genes in microarray experiments through multiple scanning and image integration.

The variability of results in microarray technology is in part due to the fact that independent scans of a single hybridised microarray give spot images that are not quite the same. To solve this problem and turn it to our advantage, we introduced the approach of multiple scanning and of image integration of microarrays. To this end, we have developed specific software that creates a virtual image that statistically summarises a series of consecutive scans of a microarray. We provide evidence that the use of multiple imaging (i) enhances the detection of differentially expressed genes; (ii) increases the image homogeneity; and (iii) reveals false-positive results such as differentially expressed genes that are detected by a single scan but not confirmed by successive scanning replicates. The increase in the final number of differentially expressed genes detected in a microarray experiment with this approach is remarkable; 50% more for microarrays hybridised with targets labelled by reverse transcriptase, and 200% more for microarrays developed with the tyramide signal amplification (TSA) technique. The results have been confirmed by semi-quantitative RT-PCR tests.

Subcutaneous Progesterone Is Effective and Safe for Luteal Phase Support in IVF: An Individual Patient Data Meta-Analysis of the Phase III Trials.

OBJECTIVE: To summarize efficacy and safety data on a new progesterone compound which is available for subcutaneous administration as compared to vaginally administered progesterone for luteal phase support in patients undergoing IVF treatment. DESIGN: Data from two randomized phase III trials (07EU/Prg06 and 07USA/Prg05) performed according to GCP standards with a total sample size of 1435 per-protocol patients were meta-analyzed on an individual patient data level. SETTING: University affiliated reproductive medicine unit. PATIENTS: Subcutaneous progesterone was administered to a total of 714 subjects and vaginal progesterone was administered to a total of 721 subjects who underwent fresh embryo transfer after ovarian stimulation followed by IVF or ICSI. The subjects were between 18 and 42 years old and had a BMI <30 kg/m2. INTERVENTIONS: Subcutaneous progesterone 25 mg daily vs. either progesterone vaginal gel 90 mg daily (07EU/Prg06) or 100 mg intravaginal twice a day (07USA/Prg05) for luteal phase support in IVF patients. MAIN OUTCOME MEASURES: Ongoing pregnancy rate beyond 10 gestational weeks, live birth rate and OHSS risk. RESULTS: The administration of subcutaneous progesterone versus intra-vaginal progesterone had no impact on ongoing pregnancy likelihood (OR = 0.865, 95% CI 0.694 to 1.077; P = n.s.), live birth likelihood (OR = 0.889, 95% CI 0.714 to 1.106; P = n.s.) or OHSS risk (OR = 0.995, 95% CI 0.565 to 1.754; P = n.s.) in regression analyses accounting for clustering of patients within trials, while adjusting for important confounders. Only female age and number of oocytes retrieved were significant predictors of live birth likelihood and OHSS risk. CONCLUSION: No statistical significant or clinical significant differences exist between subcutaneous and vaginal progesterone for luteal phase support.

Therapeutic efficacy and tolerability of the topical treatment of inflammatory conditions of the oral cavity with a mouthwash containing diclofenac epolamine: a randomized, investigator-blind, parallel-group, controlled, phase III study.

BACKGROUND: Non-steroidal anti-inflammatory drugs (NSAIDs), including diclofenac, are the mainstay of analgesic and anti-inflammatory treatment in dentistry. Diclofenac epolamine [diclofenac N-(2-hydroxyethyl)pyrrolidine; DHEP] is a diclofenac salt with greater water solubility and better cutaneous absorption properties than other commonly used forms of the drug. IBSA has recently developed a mouthwash formulation of DHEP for the topical treatment of inflammatory conditions of the oral cavity. OBJECTIVE: The aim of this study was to compare the efficacy and tolerability of DHEP mouthwash (Osmal®) with that of a reference product (commercially available diclofenac mouthwash). METHODS: This was a randomized, investigator-blind, parallel-group, controlled, phase III study that enrolled 80 patients with conditions affecting the oral cavity, characterized by an inflammatory component, and eligible for analgesic and anti-inflammatory treatment. Patients were randomized 1:1 to DHEP mouthwash (0.103% DHEP in aqueous solution) or to diclofenac mouthwash (0.074% free diclofenac in aqueous solution). The treatment regimen was the same in both groups: 1-minute rinse with 15 mL of mouthwash, twice daily for 7 days. Visits were scheduled at study inclusion (D0), and 3 days (D3) and 7 days (D7) after treatment initiation. During each visit assessments were made of pain severity (using a 5-point semi-quantitative scale and a 100-mm visual analogue scale [VAS]) and inflammatory signs (using a 5-point scale). The primary study endpoint was the change in pain severity scores from D0 to D3 and D7. Secondary endpoints included effects of treatment on inflammation score, quality of sleep, compliance with treatment and the safety and tolerability of treatment. RESULTS: The two treatment arms were homogeneous in terms of patient characteristics. The most prevalent oral condition was gingivitis. Overall both topical treatments were effective in alleviating pain and inflammation, as evidenced by decreases in pain and inflammation scores within 3 days after treatment initiation. Notably, a significantly greater proportion of patients treated with DHEP were free of pain and inflammatory symptoms at D3 compared with those treated with the diclofenac mouthwash (40% vs 20% of patients; p < 0.05). Also, DHEP was associated with more marked, but not statistically significant, decreases in VAS pain scores versus baseline after 3 days' treatment. Compliance with both treatments was good and both mouthwashes were well tolerated. CONCLUSION: DHEP mouthwash was at least as effective as diclofenac mouthwash at alleviating pain and inflammation symptoms and is well tolerated in patients with painful inflammatory conditions of the oral cavity. The potential of DHEP mouthwash deserves to be investigated in a larger patient population.

Use and misuse of antipsychotic drugs in patients with dementia in Alzheimer special care units.

The objective of this study was to estimate the prevalence of antipsychotic use and investigate their association with behavioural and psychological symptoms of dementia (BPSD) and other clinical predictors. Patients with dementia, aged 65 and above and resident in 35 Alzheimer special care units were sequentially enrolled into a 18-month prospective observational study. Data on sociodemographic, cognitive, functional, behavioural and clinical characteristics and drug exposure were collected at baseline and at 6-month intervals up to 18 months. The prevalence of antipsychotic use and the association with BPSD and clinical predictors were analysed. Of the 349 patients with dementia enrolled in the study, 209 (60%) were taking at least one antipsychotic. Risperidone and promazine were the most frequently prescribed antipsychotic; 40.7% simultaneously received a benzodiazepine, 20% an antidepressant. More than 50% were still taking antipsychotics at 18 months of follow-up. No associations were found between antipsychotic use and level of cognitive impairment, basal activity of daily living disability and comorbidity. Multivariate analysis showed that the use of antipsychotics was highest in patients in the highest quartiles of Neuropsychiatric Inventory Scale score (III quartile, odds ratio: 1.63; 95% confidence interval: 1.19-2.23; IV quartile, odds ratio: 2.27; 95% confidence interval: 1.61-3.26). This study found high rate of use of antipsychotics in patients with dementia resident in Alzheimer special care units, frequent associations with other psychotropic medications and a strong correlation with BPSD.

Gene expression profiling in dysferlinopathies using a dedicated muscle microarray.

We have performed expression profiling to define the molecular changes in dysferlinopathy using a novel dedicated microarray platform made with 3'-end skeletal muscle cDNAs. Eight dysferlinopathy patients, defined by western blot, immunohistochemistry and mutation analysis, were investigated with this technology. In a first experiment RNAs from different limb-girdle muscular dystrophy type 2B patients were pooled and compared with normal muscle RNA to characterize the general transcription pattern of this muscular disorder. Then the expression profiles of patients with different clinical traits were independently obtained and hierarchical clustering was applied to discover patient-specific gene variations. MHC class I genes and genes involved in protein biosynthesis were up-regulated in relation to muscle histopathological features. Conversely, the expression of genes codifying the sarcomeric proteins titin, nebulin and telethonin was down-regulated. Neither calpain-3 nor caveolin, a sarcolemmal protein interacting with dysferlin, was consistently reduced. There was a major up-regulation of proteins interacting with calcium, namely S100 calcium-binding proteins and sarcolipin, a sarcoplasmic calcium regulator.