Howard E. Rockette’s research while affiliated with University of Pittsburgh and other places

Background: Young children with acute otitis media (AOM) frequently exhibit nasopharyngeal colonization with either Streptococcus pneumoniae, Haemophilus influenzae or both pathogens. We aimed to determine if antibiotics could be spared or shortened in those without nasopharyngeal colonization with either pathogen. Methods: In 2 separate randomized clinical trials in children aged 6-23 months with stringently-diagnosed AOM, we performed bacterial cultures on nasopharyngeal specimens collected at the time of diagnosis. In the first trial, we compared the efficacy of amoxicillin/clavulanate (amox/clav) administered for 10 days vs. that of placebo, and in the second trial, we compared the efficacy of amox/clav administered for 10 days vs. 5 days. In each trial, we classified children as being colonized with both S. pneumoniae and H. influenzae, S. pneumoniae alone, H. influenzae alone, or neither pathogen, and as experiencing either clinical success or clinical failure at the end-of-therapy visit, based on previously reported a priori criteria. Results: We evaluated 796 children. Among children randomized to amox/clav, those colonized with either S. pneumoniae or H. influenzae or both were approximately twice as likely to experience clinical failure as children not colonized with either pathogen (odds ratio: 1.8; confidence intervals: 1.2-2.9). In contrast, among children randomized to placebo, clinical failure at the end-of-therapy visit was not associated with nasopharyngeal culture results at the time of diagnosis. Conclusions: Children colonized with either S. pneumoniae or H. influenzae or both have a greater chance of treatment failure than children colonized with neither pathogen.

Objective: To assess the efficacy and tolerability of tocilizumab in a multicenter, randomized, double-blind, placebo-controlled trial in refractory adult patients with dermatomyositis (DM) and polymyositis (PM). Methods: Thirty-six subjects with probable or definite DM/PM were enrolled in a 6-month phase 2B clinical trial and randomized 1:1 to receive tocilizumab (8 mg/kg intravenously) or placebo every 4 weeks for 24 weeks. Eligible subjects had either a DM rash, a myositis-associated autoantibody or an adjudicated PM diagnosis. Active disease was defined by at least three of six abnormal core set measures (CSMs), including a manual muscle testing (MMT)-8 score of less than 136/150. If the MMT-8 score was greater than 136, then a cutaneous score of 3 or more (10 cm visual analogue scale) was required along with three additional abnormal CSMs indicating disease activity. The primary endpoint compared the Total Improvement Score (TIS) between both arms from week 4 to 24. Secondary outcomes included time to meeting minimal TIS improvement, changes in CSMs, time to worsening, steroid-sparing effect, proportion of subjects meeting more stringent improvement criteria, and safety outcomes. Results: There was no significant difference (P = 0.86) in the TIS over 24 weeks between tocilizumab and placebo arms. The secondary endpoints of time to improvement (minimal, moderate, or major), time to worsening, CSM changes, safety outcomes, and steroid-sparing effect were also not significantly different between arms. Conclusion: Tocilizumab was safe and well tolerated but did not meet the primary or secondary efficacy outcomes in refractory DM and PM in this 24-week phase 2B study.

Background To evaluate the efficacy of adjuvant systemic corticosteroids in reducing kidney scarring. A previous study suggested that use of adjuvant systemic corticosteroids reduces kidney scarring in children radiologically confirmed to have extensive pyelonephritis. Efficacy of corticosteroids for children with febrile urinary tract infection (UTI) has not been studied.Methods Children aged 2 months to 6 years with their first febrile UTI were randomized to corticosteroids or placebo for 3 days (both arms received antimicrobial therapy); kidney scarring was assessed using 99mTc-dimercaptosuccinic acid kidney scan 5–24 months after the initial UTI.ResultsWe randomized 546 children of which 385 had a UTI and 254 had outcome kidney scans (instead of the 320 planned). Rates of kidney scarring were 9.8% (12/123) and 16.8% (22/131) in the corticosteroid and placebo groups, respectively (p = 0.16), corresponding to an absolute risk reduction of 5.9% (95% confidence interval: − 2.2, 14.1).Conclusion While children randomized to adjuvant corticosteroids tended to develop fewer kidney scars than children who were randomized to receive placebo, a statistically significant difference was not achieved. However, the study was limited by not reaching its intended sample size.Clinical Trial RegistrationClinicaltrials.gov, NCT01391793, Registered 7/12/2011 Graphical abstract

Objective: The objective was to describe the methodology used to develop new response criteria for adult DM/PM and JDM. Methods: Patient profiles from prospective natural history data and clinical trials were rated by myositis specialists to develop consensus gold-standard ratings of minimal, moderate and major improvement. Experts completed a survey regarding clinically meaningful improvement in the core set measures (CSM) and a conjoint-analysis survey (using 1000Minds software) to derive relative weights of CSM and candidate definitions. Six types of candidate definitions for response criteria were derived using survey results, logistic regression, conjoint analysis, application of conjoint-analysis weights to CSM and published definitions. Sensitivity, specificity and area under the curve were defined for candidate criteria using consensus patient profile data, and selected definitions were validated using clinical trial data. Results: Myositis specialists defined the degree of clinically meaningful improvement in CSM for minimal, moderate and major improvement. The conjoint-analysis survey established the relative weights of CSM, with muscle strength and Physician Global Activity as most important. Many candidate definitions showed excellent sensitivity, specificity and area under the curve in the consensus profiles. Trial validation showed that a number of candidate criteria differentiated between treatment groups. Top candidate criteria definitions were presented at the consensus conference. Conclusion: Consensus methodology, with definitions tested on patient profiles and validated using clinical trials, led to 18 definitions for adult PM/DM and 14 for JDM as excellent candidates for consideration in the final consensus on new response criteria for myositis.

Amoxicillin/clavulanate (A/C), is currently the most effective oral antimicrobial in treating children with acute otitis media (AOM), but standard dosage of 90/6.4 mg/kg/day commonly causes diarrhea. We examined whether an A/C formulation containing lower concentrations of clavulanate would result in less diarrhea, while maintaining plasma levels of amoxicillin and clavulanate adequate to eradicate middle-ear pathogens and achieve clinical success. We conducted an open-label study in children aged 6 to 23 months with AOM. In Phase 1, we treated 40 children with a reduced-clavulanate A/C formulation providing 90/3.2 mg/kg/day for 10 days. In Phase 2, we treated 72 children with the same formulation at a dosage of 80/2.85 mg/kg/day for 10 days. We compared these children's rates of protocol-defined diarrhea (PDD), diaper dermatitis, and AOM clinical response with rates we had reported in children who received the standard A/C regimen, and we obtained plasma levels of amoxicillin and clavulanate at various time points. Outcomes in Phase 1 children and in children who had received the standard regimen did not differ significantly. Rates of PDD in children receiving Phase 2 and standard regimens were 17% and 26%, respectively (P=0.10). Corresponding rates of diaper dermatitis were 22% and 34% (P=0.04), and of AOM treatment failure were 12% and 16% (P=0.44). Symptomatic responses did not differ significantly between regimens; both gave clavulanate levels sufficient to inhibit β-lactamase activity. In young children with AOM, clavulanate dosages lower than those currently used may be associated with fewer side-effects without reducing clinical efficacy.

To develop response criteria for adult dermatomyositis (DM) and polymyositis (PM). Expert surveys, logistic regression, and conjoint analysis were used to develop 287 definitions using core set measures. Myositis experts rated greater improvement among multiple pairwise scenarios in conjoint analysis surveys, where different levels of improvement in 2 core set measures were presented. The PAPRIKA (Potentially All Pairwise Rankings of All Possible Alternatives) method determined the relative weights of core set measures and conjoint analysis definitions. The performance characteristics of the definitions were evaluated on patient profiles using expert consensus (gold standard) and were validated using data from a clinical trial. The nominal group technique was used to reach consensus. Consensus was reached for a conjoint analysis-based continuous model using absolute per cent change in core set measures (physician, patient, and extramuscular global activity, muscle strength, Health Assessment Questionnaire, and muscle enzyme levels). A total improvement score (range 0-100), determined by summing scores for each core set measure, was based on improvement in and relative weight of each core set measure. Thresholds for minimal, moderate, and major improvement were >= 20, >= 40, and >= 60 points in the total improvement score. The same criteria were chosen for juvenile DM, with different improvement thresholds. Sensitivity and specificity in DM/ PM patient cohorts were 85% and 92%, 90% and 96%, and 92% and 98% for minimal, moderate, and major improvement, respectively. Definitions were validated in the clinical trial analysis for differentiating the physician rating of improvement (p< 0.001). The response criteria for adult DM/ PM consisted of the conjoint analysis model based on absolute per cent change in 6 core set measures, with thresholds for minimal, moderate, and major improvement.

To develop response criteria for juvenile dermatomyositis (DM). We analysed the performance of 312 definitions that used core set measures from either the International Myositis Assessment and Clinical Studies Group (IMACS) or the Paediatric Rheumatology International Trials Organisation (PRINTO) and were derived from natural history data and a conjoint analysis survey. They were further validated using data from the PRINTO trial of prednisone alone compared to prednisone with methotrexate or cyclosporine and the Rituximab in Myositis (RIM) trial. At a consensus conference, experts considered 14 top candidate criteria based on their performance characteristics and clinical face validity, using nominal group technique. Consensus was reached for a conjoint analysis-based continuous model with a total improvement score of 0-100, using absolute per cent change in core set measures of minimal (>= 30), moderate (>= 45), and major (>= 70) improvement. The same criteria were chosen for adult DM/polymyositis, with differing thresholds for improvement. The sensitivity and specificity were 89% and 91-98% for minimal improvement, 92-94% and 94-99% for moderate improvement, and 91-98% and 85-86% for major improvement, respectively, in juvenile DM patient cohorts using the IMACS and PRINTO core set measures. These criteria were validated in the PRINTO trial for differentiating between treatment arms for minimal and moderate improvement (p= 0.009-0.057) and in the RIM trial for significantly differentiating the physician's rating for improvement (p< 0.006). The response criteria for juvenile DM consisted of a conjoint analysis-based model using a continuous improvement score based on absolute per cent change in core set measures, with thresholds for minimal, moderate, and major improvement.

Objective: To develop response criteria for juvenile dermatomyositis (DM). Methods: We analyzed the performance of 312 definitions that used core set measures from either the International Myositis Assessment and Clinical Studies Group (IMACS) or the Paediatric Rheumatology International Trials Organisation (PRINTO) and were derived from natural history data and a conjoint analysis survey. They were further validated using data from the PRINTO trial of prednisone alone compared to prednisone with methotrexate or cyclosporine and the Rituximab in Myositis (RIM) trial. At a consensus conference, experts considered 14 top candidate criteria based on their performance characteristics and clinical face validity, using nominal group technique. Results: Consensus was reached for a conjoint analysis-based continuous model with a total improvement score of 0-100, using absolute percent change in core set measures of minimal (≥30), moderate (≥45), and major (≥70) improvement. The same criteria were chosen for adult DM/polymyositis, with differing thresholds for improvement. The sensitivity and specificity were 89% and 91-98% for minimal improvement, 92-94% and 94-99% for moderate improvement, and 91-98% and 85-86% for major improvement, respectively, in juvenile DM patient cohorts using the IMACS and PRINTO core set measures. These criteria were validated in the PRINTO trial for differentiating between treatment arms for minimal and moderate improvement (P = 0.009-0.057) and in the RIM trial for significantly differentiating the physician's rating for improvement (P < 0.006). Conclusion: The response criteria for juvenile DM consisted of a conjoint analysis-based model using a continuous improvement score based on absolute percent change in core set measures, with thresholds for minimal, moderate, and major improvement.

Objective: To develop response criteria for adult dermatomyositis (DM) and polymyositis (PM). Methods: Expert surveys, logistic regression, and conjoint analysis were used to develop 287 definitions using core set measures. Myositis experts rated greater improvement among multiple pairwise scenarios in conjoint analysis surveys, where different levels of improvement in 2 core set measures were presented. The PAPRIKA (Potentially All Pairwise Rankings of All Possible Alternatives) method determined the relative weights of core set measures and conjoint analysis definitions. The performance characteristics of the definitions were evaluated on patient profiles using expert consensus (gold standard) and were validated using data from a clinical trial. The nominal group technique was used to reach consensus. Results: Consensus was reached for a conjoint analysis-based continuous model using absolute percent change in core set measures (physician, patient, and extramuscular global activity, muscle strength, Health Assessment Questionnaire, and muscle enzyme levels). A total improvement score (range 0-100), determined by summing scores for each core set measure, was based on improvement in and relative weight of each core set measure. Thresholds for minimal, moderate, and major improvement were ≥20, ≥40, and ≥60 points in the total improvement score. The same criteria were chosen for juvenile DM, with different improvement thresholds. Sensitivity and specificity in DM/PM patient cohorts were 85% and 92%, 90% and 96%, and 92% and 98% for minimal, moderate, and major improvement, respectively. Definitions were validated in the clinical trial analysis for differentiating the physician rating of improvement (P < 0.001). Conclusion: The response criteria for adult DM/PM consisted of the conjoint analysis model based on absolute percent change in 6 core set measures, with thresholds for minimal, moderate, and major improvement.