Non-inferiority Analysis Research Articles

Systematic review and meta-analysis: sodium picosulfate/magnesium citrate vs. polyethylene glycol for colonoscopy preparation.

Previous studies comparing sodium picosulfate/magnesium citrate (SPMC) with polyethylene glycol (PEG) drew inconsistent conclusions. We conducted a meta-analysis to compare the performance of the two agents for colonoscopy preparation. A search of randomized controlled trials (RCTs) up to July 2015 was acquired, using MEDLINE, EMBASE, the Cochrane Library, and Google Scholar. We calculated the pooled estimates of bowel cleanliness, polyp/adenoma detection rate (PDR/ADR), completion of preparation, willingness to repeat identical bowel preparation, and adverse events by using relative risk (RR) with random-effects models. A non-inferiority analysis was performed, comparing SPMC to PEG for bowel cleaning efficacy. A total of 25 RCTs were qualified for analysis. There was no statistically significant difference between the two agents in bowel cleanliness, but the effect direction showed a trend in favor of PEG (RR 0.93; 95 % CI 0.86-1.01, P = 0.07). The non-inferiority analysis demonstrated the non-inferiority of SPMC by retaining at least 90 % of the effect of PEG. Similarly, there was no significant difference between the two agents in PDR (RR 0.94; 95 % CI 0.82-1.08, P = 0.37) and ADR (RR 0.88; 95 % CI 0.74-1.05, P = 0.16). However, a higher proportion of patients were likely to complete SPMC preparation (RR 1.08; 95 % CI 1.04-1.13, P < 0.001) and were willing to repeat SPMC preparation (RR 1.44; 95 % CI 1.25-1.67, P < 0.001). The total number of adverse events was significantly lower in the SPMC group (RR 0.78; 95 % CI 0.66-0.93, P = 0.004). SPMC, with better tolerability and less frequent adverse events, demonstrated non-inferior bowel cleaning efficacy than that of the PEG. Large-scale, well-organized, head-to-head studies are warranted.

Safety and Immunogenicity of a Quadrivalent Meningococcal Conjugate Vaccine and Commonly Administered Vaccines After Coadministration

Given the broad age range across which the quadrivalent meningococcal conjugate vaccine MenACWY-CRM is used, coadministration with routine vaccines should be evaluated across age groups for possible immunologic interference and impact on vaccine reactogenicity and safety. We summarize data from a large population of infants, adolescents and international travelers from 10 phase 3 or 4 clinical studies to evaluate coadministration of MenACWY-CRM with commonly administered vaccines. Noninferiority analyses of immune responses were performed across studies and age groups for each vaccine. Reactogenicity and safety were also assessed. In infants, MenACWY-CRM coadministered with routine vaccines did not reduce immune responses to diphtheria, tetanus, poliovirus, hepatitis B, Haemophilus influenzae type b, pneumococcal conjugate, measles-mumps-rubella, varicella or pertussis antigens. Noninferiority criteria were not met for some pneumococcal conjugate serotypes at 7 months of age, but no consistent trends were observed. In adolescents, coadministration did not reduce immune responses to tetanus, diphtheria and human papilloma virus vaccine antigens. Noninferiority criteria for pertussis antigens were not uniformly met in infant and adolescent studies, although the clinical relevance is unclear. In adults, coadministration did not reduce immune responses to hepatitis A/B, typhoid fever, yellow fever, Japanese encephalitis and rabies antigens. Immune responses to MenACWY-CRM were not impacted by coadministration of commonly administered vaccines. Coadministration did not increase frequencies of postvaccination adverse events in any age group. With no clinically relevant vaccine interactions or impact on vaccine reactogenicity or safety, these results support the coadministration of MenACWY-CRM with routine vaccines in all age groups.

Randomized non-inferiority trial of Bicalutamide and Dutasteride versus LHRH agonists for prostate volume reduction prior to I-125 permanent implant brachytherapy for prostate cancer

ObjectiveTo determine the efficacy and toxicity of a 3-month regimen of Dutasteride and Bicalutamide compared to LHRH agonists for prostate volume (PV) reduction prior to permanent implant prostate brachytherapy (PIPB). Material and methodsPatients with low-risk or low-tier intermediate risk prostate cancer eligible for PIPB with a prostate volume greater than 50cc were randomized to either Dutasteride 0.5mg Bicalutamide 50mg daily and Tamoxifen 10mg daily for 3months (D+B group) or to a 3month dose of an LHRH agonist and Bicalutamide daily for 1month (LHRH group). Their PV was measured at baseline and at pre-implant. Non-inferiority analysis was completed for the relative (%) PV reduction. IPSS and EPIC questionnaires were completed at baseline, pre-implant and at 1, 3, 6, 12, 18 and 24months post-treatment. IPSS and EPIC comparisons were based on superiority analysis Results60 patients were randomized (31 to LHRH group and 29 to D+B group). Mean relative PV reduction (SD) was 35.5% (8.9) in the LHRH group and 31.7% (9.6) in the D+B group. The upper bound of the 95% confidence for the interval for the difference between groups favouring LHRH agonists for PV reduction was 8.6 which did not cross the 10% non-inferiority margin meaning D+B is non-inferior to LHRH agonist for PV reduction, although 5/29 (17%) of those in the D+B group required longer duration of D+B to achieve adequate volume reduction. There were no statistically significant differences in IPSS scores over the entire follow-up period. EPIC sexual summary score was significantly better in the D+B group at pre-implant, 1month, 3months post-implant. ConclusionDutasteride and Bicalutamide is a regimen of non-inferior efficacy to LHRH agonist based regimens for prostate volume reduction prior to permanent implant prostate brachytherapy. D+B has less sexual toxicity compared to LHRH agonists prior to implant and for the first 6months after implant. D+B is therefore an option to be considered for prostate volume reduction prior to PIPB.

Standardised mortality ratio based on the sum of age and percentage total body surface area burned is an adequate quality indicator in burn care: An exploratory review

Standardised Mortality Ratio (SMR) based on generic mortality predicting models is an established quality indicator in critical care. Burn-specific mortality models are preferred for the comparison among patients with burns as their predictive value is better. The aim was to assess whether the sum of age (years) and percentage total body surface area burned (which constitutes the Baux score) is acceptable in comparison to other more complex models, and to find out if data collected from a separate burn centre are sufficient for SMR based quality assessment.The predictive value of nine burn-specific models was tested by comparing values from the area under the receiver-operating characteristic curve (AUC) and a non-inferiority analysis using 1% as the limit (delta). SMR was analysed by comparing data from seven reference sources, including the North American National Burn Repository (NBR), with the observed mortality (years 1993–2012, n=1613, 80 deaths). The AUC values ranged between 0.934 and 0.976. The AUC 0.970 (95% CI 0.96–0.98) for the Baux score was non-inferior to the other models. SMR was 0.52 (95% CI 0.28–0.88) for the most recent five-year period compared with NBR based data.The analysis suggests that SMR based on the Baux score is eligible as an indicator of quality for setting standards of mortality in burn care. More advanced modelling only marginally improves the predictive value. The SMR can detect mortality differences in data from a single centre.

Intermittent vs Continuous Androgen Deprivation Therapy for Prostate Cancer: A Systematic Review and Meta-analysis.

Androgen deprivation is the standard therapy for patients with advanced or recurrent prostate cancer. However, this treatment causes adverse effects, alters quality of life, and may lead to castration-resistant disease. Intermittent androgen deprivation has been studied as an alternative. To conduct a systematic review and meta-analysis comparing the efficacy and tolerability of intermittent vs continuous androgen deprivation therapy in patients with prostate cancer. We searched Cochrane CENTRAL, Medline, Embase, Web of Science, Biosis, National Technical Information Service, OpenSIGLE, and Google Scholar from inception of each database through March 2014. References from published guidelines, reviews, and other relevant articles were also considered. We selected randomized clinical trials comparing intermittent vs continuous androgen deprivation therapy in patients with prostate cancer. Two reviewers performed study selection, data abstraction, and risk of bias assessment. We calculated hazard ratios (HRs) with the inverse variance method and risk ratios with the Mantel-Haenszel method, using random effect models. A noninferiority analysis was conducted for overall survival with a margin of 1.15 for the upper boundary of the HR. We assessed heterogeneity using the I2 index. Primary outcomes were overall survival and quality of life. Secondary outcomes were cancer-specific survival, progression-free survival, time to castration resistance, skeletal-related events, and adverse effects. From 10 510 references, we included 22 articles from 15 trials (6856 patients) published between 2000 and 2013. All but 1 study had an unclear or high risk of bias. We observed no significant difference between intermittent and continuous therapy for overall survival (HR, 1.02; 95% CI, 0.93-1.11; 8 trials, 5352 patients), cancer-specific survival (HR, 1.02; 95% CI, 0.87-1.19; 5 trials, 3613 patients), and progression-free survival (HR, 0.94; 95% CI, 0.84-1.05; 4 trials, 1774 patients). There was minimal difference in patients' self-reported quality of life between the 2 interventions. Most trials observed an improvement in physical and sexual functioning with intermittent therapy. Intermittent androgen deprivation was not inferior to continuous therapy with respect to the overall survival. Some quality-of-life criteria seemed improved with intermittent therapy. Intermittent androgen deprivation can be considered as an alternative option in patients with recurrent or metastatic prostate cancer.

Safety, immune lot-to-lot consistency and non-inferiority of a fully liquid pentavalent DTwp-HepB-Hib vaccine in healthy Indian toddlers and infants

ABSTRACTPentavalent combination vaccines are important tools to strengthen the immunization programs in numerous countries throughout the world. A large number of countries have recognized the value of combination vaccines and have introduced whole cell pentavalent vaccines into their immunization programs. A phase III, multi-center, randomized, single blinded study of a fully liquid pentavalent DTwP-HepB-Hib investigational vaccine (Shan5™) was conducted across India in 2 cohorts: 15 toddlers were evaluated for safety and immunogenicity following a single booster dose (Cohort 1) followed by 1085 infants (Cohort 2) evaluated for immunogenicity and safety following 3-dose primary immunization of the investigational vaccine or a locally licensed comparator vaccine (Pentavac SD). Immune consistency analysis among 3 lots of the investigational vaccine, and immune non-inferiority analysis of pooled (3 lots) data of investigational vaccine vs. comparator vaccine were carried out in cohort 2. The vaccines demonstrated comparable safety and immune responses in cohort 1. In cohort 2, equivalent immune consistency among 3 lots was observed for all antigens except whole cell pertussis antigens, where a marginal variation was observed which was linked to the low power of the test and concluded to not have any clinical significance. Immune non-inferiority against the comparator vaccine was demonstrated for all 5 antigens. Safety results were comparable between vaccine groups. This investigational, fully-liquid, whole-cell pertussis (wP) containing new pentavalent vaccine was found to be safe and immunologically non-inferior to the licensed comparator vaccine.

Randomized noninferiority study evaluating the efficacy of 2 commercial dry cow mastitis formulations

The study objective was to compare the efficacy of 2 commercial dry cow mastitis formulations containing cloxacillin benzathine or ceftiofur hydrochloride. Quarter-level outcomes included prevalence of intramammary infection (IMI) postcalving, risk for cure of preexisting infections, risk for acquiring a new IMI during the dry period, and risk for clinical mastitis between dry off and 100d in milk (DIM). Cow-level outcomes included the risk for clinical mastitis and the risk for removal from the herd between dry off and 100 DIM, as well as Dairy Herd Improvement Association (DHIA) test-day milk component and production measures between calving and 100 DIM. A total of 799 cows from 4 Wisconsin dairy herds were enrolled at dry off and randomized to 1 of the 2 commercial dry cow therapy (DCT) treatments: cloxacillin benzathine (DC; n=401) or ceftiofur hydrochloride (SM; n=398). Aseptic quarter milk samples were collected for routine bacteriological culture before DCT at dry off and again at 0 to 10 DIM. Data describing clinical mastitis cases and DHIA test-day results were retrieved from on-farm electronic records. The overall crude quarter-level prevalence of IMI at dry off was 34.7% and was not different between treatment groups. Ninety-six percent of infections at dry off were of gram-positive organisms, with coagulase-negative Staphylococcus and Aerococcus spp. isolated most frequently. Mixed logistic regression analysis showed no difference between treatments as to the risk for presence of IMI at 0 to 10 DIM (DC=22.4%, SM=19.9%) or on the risk for acquiring a new IMI between dry off and 0 to 10 DIM (DC=16.6%, SM=14.1%). Noninferiority analysis and mixed logistic regression analysis both showed no treatment difference in risk for a cure between dry off and 0 to 10 DIM (DC=84.8%, SM=85.7%). Cox proportional hazards regression showed no difference between treatments in quarter-level risk for clinical mastitis (DC=1.99%, SM=2.96%), cow-level risk for clinical mastitis (DC=17.0%, SM=15.3%), or on risk for removal from the herd (DC=10.7%, SM=10.3%) between dry off and 100 DIM. Finally, multivariable linear regression with repeated measures showed no overall no difference between treatments in DHIA test-day somatic cell count linear score (DC=2.19, SM=2.22), butterfat test (DC=3.84%, SM=3.86%), protein test (DC=3.02%, SM=3.02%), or 305-d mature-equivalent milk production (DC=11,817kg, SM=11,932kg) between calving and 100 DIM. In conclusion, DC was noninferior to SM in effecting a cure, and there was no difference in efficacy between these 2 DCT formulations as related to all other udder health or cow performance measures evaluated between dry off and 100 DIM.

Development of a Multiplex PCR Test with Automated Genotyping Targeting E7 for Detection of Six High-Risk Human Papillomaviruses.

Cervical cancer is caused by high-risk human papillomaviruses (HPV) and viral detection tests aid in the diagnosis of precursor lesions. In the present study, a molecular test for detection of high-risk HPV DNA, called E7-HPV, was standardized and assessed in samples from women with pre-cancerous lesions. The development of the E7-HPV test for detection and genotyping of six high-risk HPV (types 16, 18, 31, 33, 45 and 52), consisted of evaluating primer quality and adjusting the multiplex PCR conditions. Primer design was based on the E7 region of each HPV, and the fluorochrome 6-FAM was added to PCR primers. Viral detection was performed by capillary electrophoresis in automated sequencer in samples obtained from 60 women (55 with ASC-H/HSIL cytology) from August to September 2013. A non-inferiority analysis was conducted with the cobas HPV test as a reference and following international guidelines for the development of new tests. The two tests had a high concordance rate in HPV16 detection (kappa=0.972), with only one discordant case (cervical intraepithelial neoplasia grade 3, negaive with cobas and positive for HPV16 by E7-HPV) and complete agreement in HPV18 detection. When comparing detection of all high-risk HPV, three cases were positive with cobas but negative with E7-HPV, and another three cases were negative with cobas but positive with E7-HPV (HPV16, 31 and 52). When we evaluate the cases initially suspected by cytology, the two tests had the same sensitivity in detection CIN2 or worse. In conclusion, the E7-HPV test has satisfactory initial results, and its development can be continued.

Improved detection of anterior fibromuscular stroma and transition zone prostate cancer using biparametric and multiparametric MRI with MRI-targeted biopsy and MRI-US fusion guidance.

The objective of this study was to analyze the potential of prostate magnetic resonance imaging (MRI) and MRI/transrectal ultrasound-fusion biopsies to detect and to characterize significant prostate cancer (sPC) in the anterior fibromuscular stroma (AFMS) and in the transition zone (TZ) of the prostate and to assess the accuracy of multiparametric MRI (mpMRI) and biparametric MRI (bpMRI) (T2w and diffusion-weighted imaging (DWI)). Seven hundred and fifty-five consecutive patients underwent prebiopsy 3 T mpMRI and transperineal biopsy between October 2012 and September 2014. MRI images were analyzed using PIRADS (Prostate Imaging-Reporting and Data System). All patients had systematic biopsies (SBs, median n=24) as reference test and targeted biopsies (TBs) with rigid software registration in case of MRI-suspicious lesions. Detection rates of SBs and TBs were assessed for all PC and sPC patients defined by Gleason score (GS)⩾3+4 and GS⩾4+3. For PC, which were not concordantly detected by TBs and SBs, prostatectomy specimens were assessed. We further compared bpMRI with mpMRI. One hundred and ninety-one patients harbored 194 lesions in AFMS and TZ on mpMRI. Patient-based analysis detected no difference in the detection of all PC for SBs vs TBs in the overall cohort, but in the repeat-biopsy population TBs performed significantly better compared with SBs (P=0.004 for GS⩾3+4 and P=0.022 for GS⩾4+3, respectively). Nine GS⩾4+3 sPCs were overlooked by SBs, whereas TBs missed two sPC in men undergoing primary biopsy. The combination of SBs and TBs provided optimal local staging. Non-inferiority analysis showed no relevant difference of bpMRI to mpMRI in sPC detection. MRI-targeted biopsies detected significantly more anteriorly located sPC compared with SBs in the repeat-biopsy setting. The more cost-efficient bpMRI was statistically not inferior to mpMRI in sPC detection in TZ/AFMS.

TU-AB-BRA-07: Radiomics of Breast Cancer: A Robustness Study

Purpose: Computer-extracted image phenotypes (CEIPs) are being investigated as complimentary attributes in the characterization of breast cancer in radiomics/ radiogenomics research. To be useful, CIEPs need to be robust across data obtained with different manufacturers’ MRI scanners and imaging protocols. Methods: Our research involved two HIPAA-compliant retrospectively-collected MRI datasets: Database 1 included 91 imaged breast cancers from the National Cancer Institute repository (imaged using General Electric equipment) and Database 2 included 117 breast cancers (imaged at our site using Phillips equipment). For each case, information on clinical lymph node status and histopathology on ER, PR, and Her2 receptor status was available. Each lesion underwent quantitative radiomics analysis yielding CEIPs characterizing tumor size, shape, morphology, enhancement texture, kinetic curve assessment, and enhancement variance kinetics. The robustness of CEIPs was assessed through statistical comparisons across the two datasets in terms of average CEIP values, t-test results on the subgroups of interest, and non-inferiority testing of performance in the prognostic tasks of distinguishing ER, PR, and Her2 receptor status and lymph node status using area under the receiver operating characteristic curve (AUC). Results: We failed to find any statistically significant differences in the average value of the CEIP distributions across the 2 scanners for subgroups possessing enough cases. We found greater variation in average feature values for the clinical subgroups having less than 20 cases. Non-inferiority analysis demonstrated varying degrees of robustness for different MRI phenotypes. The most enhancing volume and total rate variation showed the best agreement with absolute value of the lower bound of the 90% confidence for delta AUC<0.02. Conclusion: MRI phenotypes appeared robust in their average values across MRI scanners given large enough datasets. Statistical analysis revealed the robust phenotypes in cancer subtype classification. In future work, larger data sets will be collected and robustness of CEIP further investigated. Supported, in part, by the National Institute of Biomedical Imaging and Bioengineering of the National Institutes of Health under grant number T32 EB002103.

An international collaboration for comparison of two approaches to surgical staging of low-risk endometrial cancer

patients who underwent laparoscopic hysterectomy for endometrial cancer or EIN by one of four gynecologic oncologists in a single tertiary care academic hospital between 2011 and 2013. Frequencies of SDD, and postoperative complications were evaluated longitudinally over the study periods. Rapid adoption of routine SDD within the institution was conceptualized as a natural experiment, and a noninferiority analysis, with composite postoperative complications as the outcome of interest, was conducted using a two one-sided test approach with an equivalence margin set at 7%. A multivariate logistic regression model was also constructed to evaluate the association between SDD and postoperative complications. Results: Six hundred ninety-four patients were included in the study. All patients underwent laparoscopic hysterectomy, 38.2% had pelvic and 3.0% had para-aortic lymphadenectomy, and 9.4% underwent omentectomy. The rate of SDD increased from 3.9% in the first quarter of 2011 to 70.9% in the final quarter of 2013 (P b 0.001). During this period, the frequency of postoperative readmission, unscheduled surgery, infection, and composite complications within 30 days of hysterectomy did not differ by year (P≥ 0.1 for all). The absolute risk difference in the rate of the composite complication for patients who had surgery in 2013 compared to 2011 was−3.3% (95% CI−7.7 to 1.0), which supports the hypothesis of noninferiority. Patients who had SDD were younger (mean difference = 4.1 years, P b0.001), had shorter duration of surgery (MD 28min, P b 0.001), and had fewer comorbidities (relative risk for Charlson comorbidity index N5= 0.6, P b 0.001) compared with those who were admitted. After controlling for demographic, intraoperative, and comorbid factors, patients who had SDD were not at increased risk for postoperative complications.

Degradation of CT Low-Contrast Spatial Resolution Due to the Use of Iterative Reconstruction and Reduced Dose Levels.

To determine the dose reduction that could be achieved without degrading low-contrast spatial resolution (LCR) performance for two commercial iterative reconstruction (IR) techniques, each evaluated at two strengths with many repeated scans. Two scanner models were used to image the American College of Radiology (ACR) CT accreditation phantom LCR section at volume CT dose indexes of 8, 12, and 16 mGy. Images were reconstructed by using filtered back projection (FBP) and two manufacturers' IR techniques, each at two strengths (moderate and strong). Data acquisition and reconstruction were repeated 100 times for each, yielding 1800 images. Three diagnostic medical physicists reviewed the LCR images in a blinded fashion and graded the visibility of four 6-mm rods with a six-point scale. Noninferiority and inferiority-superiority analyses were used to interpret the differences in LCR relative to FBP images acquired at 16 mGy. LCR decreased with decreasing dose for all reconstructions. Relative to FBP and full dose, 25%-50% dose reductions resulted in inferior LCR for vendors 1 and 2 for FBP and 25% dose reductions resulted in inferior and equivalent performance for vendor 1 and equivalent and superior performance for vendor 2 at moderate and strong IR settings, respectively. When dose was reduced by 50%, both IR techniques resulted in inferior LCR at both strength settings. For radiation dose reductions of 25% or more, the ability to resolve the four 6-mm rods in the ACR CT accreditation phantom can be lost.

Co-trimoxazole prophylaxis in adults, including pregnant women, with HIV: a systematic review and meta-analysis

Co-trimoxazole prophylaxis is used to reduce morbidity and mortality in people with HIV. We systematically reviewed three topics related to co-trimoxazole prophylaxis to update WHO guidelines: initiation, discontinuation, and dose. We searched PubMed, Embase, WHO Global Index Medicus, and clinical trial registries in November, 2013, for randomised controlled trials and observational studies including co-trimoxazole prophylaxis and a comparator group. Studies were eligible if they reported death, WHO clinical stage 3 or 4 events, admittance to hospital, severe bacterial infections, tuberculosis, pneumonia, diarrhoea, malaria, or treatment-limiting adverse events. Infant mortality, low birthweight, and placental malaria were additional outcomes for the comparison of co-trimoxazole prophylaxis and intermittent preventive treatment for malaria in pregnant women (IPTp). We compared a dose of 480 mg co-trimoxazole once a day with one of 960 mg co-trimoxazole once a day. We used a 10% margin for non-inferiority and equivalence analyses. We used random-effects models for all meta-analyses. This study is registered with PROSPERO, number CRD42014007163. 19 articles, published from 1995 to 2014 and including 35 328 participants, met the inclusion criteria. Co-trimoxazole prophylaxis reduced rates of death (hazard ratio [HR] 0·40, 95% CI 0·26-0·64) when started at CD4 counts of 350 cells per μL or lower with antiretroviral therapy (ART) worldwide. Co-trimoxazole prophylaxis started at higher than 350 cells per μL without ART reduced rates of death (0·50, 0·30-0·83) and malaria (0·25, 0·10-0·57) in Africa. Co-trimoxazole prophylaxis was non-inferior to IPTp with respect to infant mortality (risk difference [RD] -0·05, 95% CI -0·12 to 0·02), low birthweight (0·00, -0·07 to 0·07), and placental malaria (0·00, -0·10 to 0·10). Co-trimoxazole prophylaxis continuation after ART-induced recovery with CD4 counts higher than 350 cells per μL reduced admittances to hospital (HR 0·42, 95% CI 0·22-0·80), pneumonia (0·73, 0·61-0·88), malaria (0·03, 0·01-0·10), and diarrhoea (0·61, 0·48-0·78) in Africa. A dose of 480 mg co-trimoxazole prophylaxis once a day did not reduce treatment-limiting adverse events compared with 960 mg once a day (RD -0·07, 95% CI -0·52 to 0·39). Co-trimoxazole prophylaxis should be given with ART in people with CD4 counts of 350 cells per μL or lower in low-income and middle-income countries. Co-trimoxazole prophylaxis should be provided irrespective of CD4 count in settings with a high burden of infectious diseases. Pregnant women with HIV in Africa should use co-trimoxazole rather than IPTp to prevent malaria complications in infants. Further research is needed to inform dose optimisation and co-trimoxazole use in the context of expanded ART in different epidemiological settings. None.

A Comparative Study between Hyaluronic Acid and Corticosteroids for the Treatment of the Greater Trochanteric Pain Syndrome

Objective: To date, there are no studies addressing the efficacy of hyaluronic acid (HA) injections at the trochanteric bursa in patients with greater trochanteric pain syndrome (GTPS). The objective of the study was to compare the efficacy and safety of HA to corticosteroid injections for the treatment of the GTPS. Methods: This prospective, randomized, two-arm trial involved 47 patients with unilateral or bilateral GTPS. Patients received an intra-bursal injection of 40 mg triamcinolone acetonide plus 1mL lidocaine, or of 60 mg HA. Patients completed visual analog scales (VAS) and Likert scales to evaluate interference of pain with daily activity, recovery from pain, and treatment satisfaction. A non-inferiority analysis was also performed. Results: Mean VAS score for pain significantly decreased comparing baseline with 1, 3 and 6 months in both treatment groups. VAS score for pain on palpation was also significantly lower than baseline in both arms. No significant differences were found between groups. Analysis of Likert scales at the sixth month didn’t detect statistically significant differences between treatment groups. The non-inferiority analysis showed that the treatment with HA was non-inferior to corticosteroids. No secondary adverse effects were found among the patients of both groups during the follow-up. Conclusions: The treatment with HA has demonstrated to be non-inferior to corticosteroids after 6 months of follow-up in patients with GTPS. Therefore, the treatment with HA may be considered an effective alternative therapeutic strategy to reduce pain in patients in whom the treatment with corticosteroids, or other therapies, have been unsuccessful or contraindicated.

Etifoxine versus alprazolam for the treatment of adjustment disorder with anxiety: a randomized controlled trial.

BackgroundAdjustment disorder with anxiety (ADWA) is a highly prevalent condition, particularly in primary care practice. There are relatively few systematic treatment trials in the area of ADWA, and there are few data on predictors of treatment response. Etifoxine is a promising agent insofar as it is not associated with dependence, but in primary care settings benzodiazepines continue to be frequently prescribed for psychiatric symptoms. A randomized controlled trial of etifoxine versus alprazolam for ADWA was undertaken, focusing on efficacy and safety measures, and including an investigation of predictors of clinical response.MethodsThis was a comparative, multicenter, double-blind, randomized trial in two parallel groups of outpatients with ADWA. One group was treated with 150 mg/day for etifoxine, and the other with 1.5 mg/day for alprazolam for 28 days. Patients were followed for 4 weeks of treatment, and for an additional week after treatment discontinuation. The primary outcome measure was the Hamilton Anxiety Rating Scale (HAM-A), while secondary outcome measures included the Sheehan Disability Scale (SDS), the Clinical Global Impressions-Change Scale (CGI-C), and the Self-Report for the Assessment of Adjustment Disorders. Non-inferiority analysis was used to assess the primary outcome measure, and a multivariate logistic regression was employed to investigate predictors of response.ResultsTwo hundred and two adult outpatients with ADWA were enrolled at 17 primary care sites. One hundred and seventy seven patients completed the study (n = 87 in the etifoxine group; n = 90 in the alprazolam group). Etifoxine and alprazolam were accompanied by decreases in the HAM-A at day 28, with a difference between treatment groups in HAM-A score of 1.78 [90% CI; 0.23, 3.33] in favor of alprazolam. However, after medication discontinuation, HAM-A scores continued to improve in the etifoxine group, but increased in the alprazolam group; the difference between groups in mean change between day 28 and day 35 was significant (p = 0.019). Secondary outcome measures showed similar results for etifoxine and alprazolam at day 35. More treatment-related adverse events were reported in patients treated with alprazolam, particularly central nervous system-related AEs, and especially after medication discontinuation. No significant predictors of treatment response were found.ConclusionThis randomized controlled trial provides support for the efficacy and safety of etifoxine in the management of adjustment disorder with anxiety, particularly when treatment discontinuation data are also assessed. Etifoxine has the important clinical advantage of having anxiolytic effects, which are not being associated with dependence. Pharmacotherapy was equally efficacious in patients with more severe anxiety symptoms at baseline. Additional work using longer-term follow-up and collecting data on cost-efficiency of management options would further advance the field of ADWA.FundingSponsorship and article processing charges for this study were provided by Biocodex, Gentilly, France.Electronic supplementary materialThe online version of this article (doi:10.1007/s12325-015-0176-6) contains supplementary material, which is available to authorized users.

Efficacy and safety of etifoxine versus alprazolam in the management of adjustment disorder with anxiety (ADWA)

BackgroundWell-conducted treatment trials and data on predictors of treatment response are both lacking for ADWA, despite the high prevalence of the condition. While benzodiazepines are frequently prescribed for anxiety disorders, etifoxine is also an effective agent not associated with dependence. A randomized controlled trial of etifoxine versus alprazolam for ADWA was undertaken, aiming at comparing efficacy and safety of the two treatments, and investigating predictors of the clinical response.MethodsTwo hundred and two adult outpatients with ADWA were enrolled at primary care settings sites in South Africa. Patients were followed for 4 weeks of treatment, and for an additional week after treatment discontinuation. The primary outcome measure was the Hamilton Anxiety Rating Scale (HAM-A) and was assessed by using a non-inferiority analysis. Secondary outcomes included the Sheehan Disability Scale (SDS) and the Clinical Global Impressions-Change Scale (CGI-C). Predictors of response were investigated with a multivariate logistic regression.ResultsBoth etifoxine and alprazolam dramatically decreased the HAM-A score at 4 weeks. The difference between treatment groups in HAM-A was of 1.78 [90% CI; 0.23, 3.33] in favor of alprazolam. The two treatments were equally efficacious in patients with more severe anxiety symptoms at baseline. Between week 4 and week 5, after treatment discontinuation, HAM-A scores continued to improve in the etifoxine group, but increased in the alprazolam group (P = 0.019); no difference was found between the two groups regarding the secondary outcomes. No significant predictors of treatment response were found. Patients treated with alprazolam experienced more treatment-related adverse events, mostly of central nervous origin, and especially after medication discontinuation.ConclusionThis trial confirms the efficacy and safety of etifoxine in the management of ADWA.

Virtual single-source computed tomography using dual-source acquisition: a new technique for the dose-neutral intraindividual comparison of different scan protocols.

The objective of this study was to compare the image quality of a standard single-source (SSS) computed tomography (CT) with that of a virtual single-source CT (VSS-CT) data set reconstructed from 2 raw data sets obtained by dual-source CT acquisition in abdominal CT to establish a radiation dose-neutral approach for the intraindividual comparison of 3 acquisition protocols at different radiation dose levels (RDLs). An abdominal phantom representing an 80-kg male was imaged using dual-source CT (SOMATOM Definition; Siemens Healthcare) at 3 RDLs with 120 kV(p) and different tube currents (low, standard, and high milliampere-second protocol). For each RDL, raw data were obtained once in single-source mode using x-ray tube A only and 5 times in dual-source mode using different ratios for tube current of x-ray tubes A and B (same total radiation dose; A/B: 90%/10%, 80%/20%, 70%/30%, 60%/40%, 50%/50%). For each RDL, SSS-CT and 5 virtual single-source image data sets (VSS-CT50 - 90) were reconstructed. To compare SSS-CT and VSS-CT data sets, image quality was assessed in terms of high- and low-contrast performance by calculating the modulation transfer function, image noise, noise power spectrum, and, for low contrast lesion detectability, the modified multiscale structural similarity index (MS-SSIM*). A maximum decrease of Δ = 5% of image quality compared with SSS-CT was defined as acceptable, and a noninferiority analysis with Δ was performed. For modulation transfer function, noninferiority was observed for all VSS-CT data sets and RDL (P < 0.05). Image noise demonstrated an acceptable increase (<3.2%, P < 0.05) for each RDL and noise power spectrum showed only minor differences in the midfrequency range. The MS-SSIM* index demonstrated for the high RDL protocol a minor decrease for VSS-CT data sets (<2%, P < 0.05). For the standard and low RDL, the relative differences of the MS-SSIM* index increased and were only in 1 case above Δ (standard RDL, mean VSS-CT80 5.1%, P > 0.05). The image quality obtained by virtual and SSS reconstruction using equivalent total radiation exposure to the patient showed only negligible differences in image quality. Therefore, this technique might allow an intraindividual comparison of full and reduced radiation dose protocols within 1 image acquisition step by simply splitting the radiation dose between the 2 x-ray tubes of a dual-source CT.

609TiP - The Idea (International Duration Evaluation of Adjuvant Chemotherapy) Collaboration: a Prospective Pooled Non-Inferiority Analysis of > 11,500 Patients from 6 Phase III Trials of Adjuvant Therapy Duration with Folfox (Folfox4 or Mfolfox6) or Xelox (3 Vs. 6 Months) for Stage III Colon Cancer

ABSTRACT Background: The IDEA collaboration was established to prospectively pool and analyse data from 6 randomized trials to answer whether 3-months of oxaliplatin-based adjuvant therapy (FOLFOX4/modified FOLFOX6 or XELOX) is non-inferior to the current standard 6-month treatment in pts with stage III colon cancer, with a primary endpoint of 3 years disease-free survival. A 3 month duration of oxaliplatin-based adjuvant therapy would provide substantial advantages in toxicity, cost, and patient convenience. Design: Members of the IDEA have agreed to pool data from their individual trials (SCOT-UK led with accrual from Australia, Denmark, Spain, Sweden & New Zealand, final accrual 4027 pts; TOSCA-Italy, final 2436 pts; GERCOR/PRODIGE-France, final 2000 pts; CALGB/SWOG-US/Canada, current accrual 1600 pts; ACHIEVE-Japan, final 1200 pts; HORG-Greece, current 600 pts) to allow a definitive analysis. IDEA members prospectively agreed on eligibility criteria, treatment administration, primary endpoints, and statistical analysis plan. May 1, 2014 total IDEA accrual exceeds 11,500 pts. This sample size will provide 3390 DFS events to provide 90% power to declare non-inferiority, based on an expected 3 year DFS rate in the control group of 72%, with a one-sided alpha of 0.025 if the true DFS HR is 1.12. A single pooled interim analysis, conducted by an external Data Monitoring Board (DMB), is prospectively specified when 50% of planned DFS events have been observed; this analysis occurred in May 2014 and the DMB recommended the trial continue per protocol with no modifications. Disclosure: T. Yoshino: Research funding provided by Yakult Honsha. All other authors have declared no conflicts of interest.

Combined glucosamine and chondroitin sulfate, once or three times daily, provides clinically relevant analgesia in knee osteoarthritis.

We compared the analgesic efficacy and safety of glucosamine sulfate (GS) and chondroitin sulfate (CS) capsules or sachet preparations with glucosamine hydrochloride (GH) and CS capsules in knee osteoarthritis (OA) patients. 1,120 subjects with radiographic knee OA (Kellgren/Lawrence 2-3) were randomized (1:1:1) at 16 centers to receive GS 500 mg/CS 400 mg three times daily capsules (GI) or once daily sachet (GII) or GH 500 mg/CS 400 mg three times daily (GIII) for a 16-week trial. Primary outcome, intention-to-treat (ITT) was change from baseline of patient reported pain intensity (0-100 mm visual analogue scale) in the affected knee and variation of Lequesne's index (LI). Monthly secondary outcomes were changes from baseline in patient reported pain and LI, patient and physician global assessments of disease activity, acetaminophen consumption, and adherence. ITT population comprised 302, 301, and 306 patients in GI, GII, and GIII. Pain significantly decreased (GI = -30.9 ± 1.5; GII = -28.7 ± 1.5; GIII = -29.7 ± 1.5 mm) in all groups (P < 0.001) as well as LI (GI = -3.8 ± 0.2; GII = -3.7 ± 0.2; GIII = -3.9 ± 0.2; P < 0.001). All secondary outcomes improved (P < 0.005) for all groups. Patients that did not complete the study were 77 (44.8 %) for lack of adherence, 16 (9.3 %) consent withdrawal, 11 (6.4 %) adverse events, eight (4.7 %) lost to follow-up, and 17 (9.9 %) for other causes. Non-inferiority analysis found no differences among groups. This is a large study showing that GS/CS and GH/CS provide clinically meaningful and sustained analgesia in knee OA regardless of dose fractionation and capsule or sachet formulations.

Changes in emotion regulation in adults with and without a history of childhood abuse following posttraumatic stress disorder treatment.

This study compared changes in emotion regulation and trait affect over the course of PTSD treatment with either prolonged exposure (PE) therapy or sertraline in adults with and without a history of childhood abuse (CA). Two hundred adults with PTSD received 10 weeks of PE or sertraline. Emotion regulation and trait affect were assessed pre- and posttreatment and at 6-month follow-up with the Emotion Regulation Questionnaire (Gross & John, 2003), the Negative Mood Regulation Scale (Catanzaro & Mearns, 1990), and the Positive and Negative Affect Schedule (Watson, Clark, & Tellegen, 1988). Individuals with and without a history of CA did not differ from one another at pretreatment on PTSD severity, emotion regulation, or positive/negative affect. In addition, treatment was effective at improving emotion regulation and trait affect in those with and without a history of CA, and no significant differences in emotion regulation or trait affect emerged posttreatment or at 6-month follow-up between adults with and without a history of CA. Furthermore, noninferiority analyses indicated that the emotion regulation and trait affect outcomes of individuals with a history of CA were no worse than those of individuals without a history of CA. These findings cast doubt on the assumption that CA is associated with worse emotion regulation following PTSD treatment, arguing against assertions that a history of CA itself is a contraindication for traditional PTSD treatment, and that there is a clear necessity for additional interventions designed to target assumed emotion regulation deficits. [Corrected]