Predefined Equivalence Margin Research Articles

Effect of Formula Composition on the Development of Infant Gut Microbiota

Breast-feeding induces a gut microbiota rich in bifidobacteria, whereas formula-fed babies have a more diverse colonization. This ecosystem contributes to the development of the immune response and the lower incidence of diarrhea and allergy in breast-fed infants. This randomized double-blind controlled trial aimed to evaluate the bifidogenic effect of a mainly whey protein study formula low in phosphate and protein, allowing a composition closer to that of human milk. One hundred ninety healthy infants exclusively received study formula with or without Bifidobacterium longum (BL999), or a control formula for up to 4 months. Breast-fed infants served as a reference population. Stool samples collected at 2 months of age were analyzed for bacterial counts (log colony-forming unit [CFU]/g). Bifidobacteria counts were significantly higher in infants receiving the study formula alone (10.0[0.8], P < 0.0001, median [interquartile range]) or with BL999 (9.8[1.4], P < 0.01) than control (9.2[3.5]), and were similar to breast-fed infants (10.1[0.4], P > 0.05). The difference between the 2 study groups was 0.16 log CFU/g (90% confidence interval [CI] [0-0.4]), within the predefined equivalence margin. Microbiota profile, as a percentage of total bacteria counts, showed about 50% Bifidobacteria, 8% Enterobacteria, and <10% Clostridia in study formulae and breast-fed infants versus 22%, 13%, and 19% in controls, respectively. There were no significant differences in growth measurements, digestive tolerance, and adverse events between groups. This study showed that infant formula closer resembling human milk was more bifidogenic than the control formula and led to a microbiota profile similar to that for breast-fed infants.

Comparison of Certolizumab Pegol with Other Anticytokine Agents for Treatment of Rheumatoid Arthritis: A Multiple-treatment Bayesian Metaanalysis

To compare the clinical efficacy of certolizumab pegol (CZP) with that of other anticytokine agents indicated for the treatment of rheumatoid arthritis (RA) with identical therapeutic indication (anti-tumor necrosis factor-α, anti-interleukin 1 or 6), with the objective of determining the noninferiority of CZP. A systematic review was performed to identify randomized controlled trials that assessed the efficacy of anticytokine agents in combination with conventional disease-modifying antirheumatic drugs (DMARD) after 6 months of treatment, using the American College of Rheumatology (ACR) response criteria, in patients with RA who have shown inadequate response to DMARD including methotrexate. Indirect treatment comparisons were carried out by a multiple-treatment Bayesian random-effects metaanalysis. Data were analyzed using the Markov chain Monte Carlo simulation. Noninferiority of CZP was assessed in comparison with a predefined equivalence margin of 5%. Nineteen placebo-controlled studies were identified: 14 evaluated the efficacy of 5 anti-TNF-α agents (infliximab, etanercept, adalimumab, golimumab, CZP) and 5 evaluated efficacy of 2 anti-interleukin agents (anakinra, tocilizumab). Every treatment showed significant efficacy versus placebo in individual studies. The multiple-treatment metaanalysis showed a highest OR for CZP on ACR20 response. Metaanalysis indicates that the efficacy of CZP according to ACR20 response is superior to that of infliximab, adalimumab, and anakinra, and equivalent or superior to that of etanercept, golimumab, and tocilizumab. According to ACR50 response, the efficacy of CZP is equivalent or superior to that of all other anticytokines. Results of this original multiple-treatment Bayesian metaanalysis indicate that certolizumab pegol is at least as efficacious as the preexisting antirheumatic anticytokine biotherapies.

Corifollitropin alfa for ovarian stimulation in IVF: a randomized trial in lower-body-weight women

In this double-blind, double-dummy, randomized, equivalence trial (Ensure), 396 women weighing 60kg or less who underwent controlled ovarian stimulation prior to IVF or intracytoplasmic sperm injection were randomized in a 2:1 ratio to a single dose of 100mug corifollitropin alfa or daily 150IU recombinant FSH (rFSH) for the first 7days of stimulation in a gonadotrophin-releasing hormone antagonist protocol. The mean +/- SD number of oocytes retrieved per started cycle was 13.3 +/- 7.3 for corifollitropin alfa versus 10.6 +/- 5.9 for rFSH. The estimated treatment difference of +2.5 oocytes (95% CI 1.2-3.9) in favour of corifollitropin alfa (P<0.001) was well within the predefined equivalence margin. The median (range) duration of stimulation was 9 (6-15) days in both groups. In 32.8% of the patients, one injection of corifollitropin alfa was sufficient to reach the human chorionic gonadotrophin criterion. The incidence of moderate and severe ovarian hyperstimulation syndrome was 3.4% for corifollitropin alfa and 1.6% for rFSH. A dose of 100mug corifollitropin alfa offers a simplified treatment option for potential normal responder patients with a lower body weight.

Clinical Equivalence of Controlled-Release Oxycodone 20 mg and Controlled-Release Tramadol 200 mg after Surgery for Breast Cancer

Aims: To assess clinical equivalence of 20 mg controlled-release oxycodone (Oxygesic®; Mundipharma, Limburg, Germany) and 200 mg controlled-release tramadol (Tramal long®; Grünenthal, Aachen, Germany) on a 12-hour dosing schedule in a randomized, double-blinded study of 54 ASA I–III physical status (American Society of Anesthesiologists classification of physical status) patients undergoing surgery for breast cancer. Methods: General anesthesia using remifentanil and propofol was performed for surgery. Patients were randomly allocated to 2 groups, receiving either 20 mg controlled-release oxycodone (Oxy group) or 200 mg controlled-release tramadol (Trama group) with the premedication (7.5 mg midazolam) and again 12 hours later. All patients had access to rescue medication (i.v. paracetamol). The primary variables for clinical equivalence were the differences between the mean values for pain scores at rest and pain scores on coughing over 24 hours after operation. The equivalence margin was determined as ±10 on the visual analogue scale. Results: Fifty-four patients were enrolled. Regarding pain scores at rest, the 90% CI of the mean differences between the treatment groups over 24 hours after operation was found to be within the predefined equivalence margin [–4.5 to +1.7], and the CI values for pain scores on coughing [–6.2 to +1.7] were similar. Cumulative paracetamol given over the 24-hour observation period did not differ significantly between the Oxy group (1.32 ±1.9 g) and the Trama group (1.61 ± 1.1 g; p = 0.32). There were no significant differences between the treatment groups regarding adverse events such as nausea (p = 0.13), vomiting (p = 0.24) and itching (p = 0.77). Also, no differences were found concerning patient satisfaction scores (p = 0.8) or patients’ general perception of postoperative pain management (p = 0.71). Conclusion: 20 mg controlled-release oxycodone is clinically equivalent to 200 mg controlled-release tramadol for postoperative analgesia after surgery for breast cancer.

Mapping the eight-item Parkinson’s Disease Questionnaire (PDQ-8) to the EQ-5D utility index

To develop a function for mapping the eight-item Parkinson's Disease Questionnaire (PDQ-8) to the EuroQol Group's EQ-5D utility index. Data from two surveys of 324 patients with Parkinson's disease was divided into two groups. One was used to estimate the mapping functions by regression methods and the other was used to validate the mapping functions. A regression model with a non-linear trend explained 55% of the variation in EQ-5D utility values and had a mean absolute deviation (MAD) of 0.083. A regression model assuming a linear trend explained 52% of the variation and had an MAD of 0.085. In the validation sample, predicted values based on the aforementioned models respectively explained 42 and 44% of the variation in the observed EQ-5D utility values and both had MADs of about 0.1. The confidence intervals of the mean difference between these predicted values and the observed values totally fell within the pre-defined equivalence margin of 0.03 points. These predicted values were also similar to the observed EQ-5D utility values in terms of their association with clinical variables. At the group level, but not at the individual level, the mapping functions can accurately map the PDQ-8 outcomes to the EQ-5D utility index.

Clinical effectiveness of usual care with or without antidepressant medication for primary care patients with minor or mild-major depression: a randomized equivalence trial

BackgroundMinor and mild-major depression are highly prevalent in primary care. There is insufficient evidence for the effectiveness of antidepressants in the treatment of minor and mild-major depression. We compared the effectiveness of usual primary care treatment, with or without antidepressants, in minor and mild-major depression.MethodsA pragmatic patient-randomized equivalence trial with 52 weeks follow-up was conducted in The Netherlands. In total, 59 primary care physicians (PCPs) recruited and treated 181 adult patients with minor or mild-major depression. Patients were randomized to four consultations within 3 months of usual care plus antidepressants (UCandAD) or usual care alone (UCnoAD). The Montgomery Åsberg Depression Rating Scale (MADRS) was used to assess changes in severity of depressive symptoms. The predefined equivalence margin was set at five points. Multilevel analysis was used to analyze the data. Secondary outcome measures were the Short-Form 36 (SF-36), and the Client Satisfaction Questionnaire (CSQ-8).ResultsPatients received on average 3.0 (SD 1.4) 15-min consultations within 3 months with (n = 85) or without paroxetine (n = 96). Equivalence of UCandAD and UCnoAD was demonstrated in the intention-to-treat analyses as well as the per-protocol analysis after 6 weeks, but not at 13, 26 and 52 weeks follow-up. No statistical differences in effectiveness between treatment groups were found in the intention-to-treat analysis. No differences in the physical and mental functioning (SF-36) were found between the treatment groups. Patients allocated to UCandAD were slightly more satisfied with their treatment at 13 weeks follow-up (but not at 52 weeks follow-up) than patients allocated to UCnoAD. Preliminary analyses suggested that subgroups such as patients with mild-major (instead of a minor) depression might benefit from antidepressant treatment. Patients who were assigned to their preferred treatment (in particular to UCnoAD) were more often compliant and had better clinical outcomes.ConclusionUCandAD was as effective as UCnoAD over the first 6 weeks, but not at 13, 26, and 52 weeks. However, superiority of either treatment could not be demonstrated either. The question whether antidepressants add any clinical effect to usual care remains unresolved. We recommend future studies to look for subgroups of patients who may benefit from antidepressants.Trial registrationDutch Trial Registry ISRCN03007807.

Are English- and Chinese-language versions of the SF-6D equivalent? A comparison from a population-based study

Objective: The goal of this study was to assess the equivalence of English- and Chinese-language versions of the SF-6D (a 6-dimensional health classification system based on the 36-Item Short Form Health Survey) using a model of equivalence proposed previously.Methods: We analyzed data from a previously published, cross-sectional, population-based survey of ethnic Chinese in Singapore, using linear regression models to adjust for the influence of potential confounding variables. Based on equivalence clinical trial methods, measurement (ie, scale) and item equivalence were assessed by comparing 90% CIs of differences in scores due to language with predefined equivalence margins, that corresponded to the minimum clinically important difference for SF-6D utility and item scores.Results: Data from 2558 respondents (aged 21–65 years; 48.8% completed the English-language version) were analyzed. The utility scores of respondents using the English- or Chinese-language versions of the SF-6D had similar distribution patterns, with a mean (SD) utility score of 0.8 (0.12). Adjusted 90% CIs for differences in utility and item scores due to language fell within predefined equivalence margins, suggesting measurement and item level equivalence. The 90% CI for scale scores was −0.0089 to 0.0065 (range, 0.0154; equivalence margin, 0.033); the 90% CI for item scores varied from −0.0046 to −0.0020 (range, 0.0026; equivalence margin, 0.0036) for vitality to −0.0024 to 0.0037 (range, 0.0061; equivalence margin, 0.0088) for social functioning. Functional equivalence was suggested because the various aspects of equivalence proposed previously were demonstrated in this study.Conclusions: English- and Chinese-language versions of the SF-6D demonstrated item, measurement, and functional equivalence in this population-based study comparing 2 widely used languages with very different linguistic structures. This suggests that English and Chinese SF-6D scores can be pooled, thus increasing the representativeness and power of studies using the SF-6D, and providing a basis for studies to value health by obtaining SF-6D utility scores in Asian populations.