Comparative Assessment of the Different American College of Rheumatology/European League Against Rheumatism Remission Definitions for Rheumatoid Arthritis for Their Use as Clinical Trial End Points.

OBJECTIVE: The American College of Rheumatology (ACR) and the European League Against Rheumatism (EULAR) have defined remission using Boolean- or index-based criteria (i.e., a Simplified Disease Activity Index [SDAI] score of ≤3.3). We undertook this study to compare definitions of remission to inform choice of end points for future rheumatoid arthritis (RA) clinical trials, and we also included in our comparison the remission criterion of a score of ≤2.8 on the Clinical Disease Activity Index (CDAI). METHODS: We performed post hoc analyses on clinical remission rates using data from 2 infliximab trials (the ASPIRE [Active-Controlled Study of Patients Receiving Infliximab for the Treatment of Rheumatoid Arthritis of Early Onset] and ATTRACT [Anti-Tumor Necrosis Factor Trial in Rheumatoid Arthritis with Concomitant Therapy] trials) and 1 golimumab trial (the GO-FORWARD trial). We investigated stringency of the different remission definitions, their power to discriminate between active drug and comparator, and aspects of their internal and external validity. We also investigated population determinants of discriminatory power for a particular remission end point. RESULTS: In patients with early RA (the ASPIRE trial), ACR/EULAR Boolean, CDAI, and SDAI remission rates at 6-7 months were 4-6% for methotrexate (MTX) alone versus 11-14% for infliximab plus MTX. In patients with MTX-refractory active RA (the ATTRACT and GO-FORWARD trials), remission rates were ≤1% for comparator (add-on of placebo) versus 4-6% for add-on of infliximab in the ATTRACT trial and ≤3% for comparator (add-on of placebo) versus 11-13% for add-on of golimumab in the GO-FORWARD trial. Existing remission cut points of different measures were generally comparable, with the Boolean criteria being somewhat more stringent than the SDAI and CDAI criteria. Remission rates were similar across definitions, as was average statistical power (CDAI, 55.6%; Boolean, 59.9%; SDAI, 62.6%). CONCLUSION: Remission is an ambitious primary end point for RA clinical trials, to be reserved for selected scenarios based on power considerations. The ACR/EULAR definitions are interchangeable, with slightly higher stringency of Boolean criteria over index-based criteria.

Comparison of three enthesitis indices in a multicentre, randomized, placebo-controlled trial of golimumab in ankylosing spondylitis (GO-RAISE).

OBJECTIVE: To compare the abilities of three enthesitis indices to detect improvement in entheseal tenderness with the TNF antagonist golimumab in AS. METHODS: Adult patients with active AS were randomly assigned to receive s.c. injections of placebo or golimumab (50 or 100 mg) every 4 weeks. Patients with inadequate week 16 responses were switched (blinded) from placebo to golimumab 50 mg or from golimumab 50 mg to 100 mg. At week 24, all patients still receiving placebo crossed over to golimumab 50 mg. Enthesitis data through week 52 are reported herein. Enthesitis was measured by a trained, independent assessor who recorded the presence or absence of tenderness in 27 entheses, which allowed simultaneous determination of three different indices [12-point Berlin Index, 17-point University of California, San Francisco (UCSF) Index and 13-point Maastricht AS Enthesitis Score (MASES)]. RESULTS: Three hundred and fifty-six AS patients were randomized to placebo (n = 78), golimumab 50 mg (n = 138) or golimumab 100 mg (n = 140); 355 had enthesitis data available for analysis. Using the UCSF Index, significant improvement from baseline vs placebo was observed for golimumab 100 mg at weeks 14 and 24. Using the MASES, significant improvement for golimumab 100 mg vs placebo at week 14 and a trend toward improvement at week 24 were observed. Using the Berlin Index, significant improvement for golimumab 100 mg vs placebo at week 14 was observed. Effect size determinations for changes to weeks 14, 24 and 52, respectively, in the Berlin (-0.27, -0.34, -0.42), UCSF (-0.44, -0.61, -0.55) and MASES (-0.30, -0.55, -0.39) indices suggested small to moderate effect sizes. CONCLUSION: In patients with active AS, the UCSF Index appeared most sensitive in detecting the effect of golimumab 100 mg vs placebo on enthesitis. TRIAL REGISTRATION: clinicaltrials.gov, http://www.clinicaltrials.gov, NCT00265083.

Age-specific questionnaires distinguish GERD symptom frequency and severity in infants and young children: development and initial validation.

Two gastroesophageal reflux disease (GERD) symptom questionnaires were developed and tested prospectively in a pilot study conducted in infants (1 through 11 months) and young children (1 through 4 years) with and without a clinical diagnosis of GERD. A pediatric gastroenterologist made the clinical diagnosis of GERD. Parents or guardians at 4 study sites completed the questionnaires, providing information on the frequency and severity of symptoms appropriate to the 2 age cohorts. In infants, symptoms assessed were back arching, choking or gagging, hiccups, irritability, refusal to feed and vomiting or regurgitation. In young children, symptoms assessed were abdominal pain, burping or belching, choking when eating, difficulty swallowing, refusal to eat and vomiting or regurgitation. Respondents were asked to describe additional symptoms. Symptom frequency was the number of occurrences of each symptom in the 7 days before completion of the questionnaire. Symptom severity was rated from 1 (not at all severe) to 7 (most severe). An individual symptom score was calculated as the product of symptom frequency and severity scores. The composite symptom score was the sum of the individual symptom scores. The mean composite symptom and individual symptom scores were higher in infants (P<0.001 and P<0.05, respectively) and young children (P<0.001 and P<0.05, respectively) with GERD than controls. Vomiting/regurgitation was particularly prevalent in infants with GERD (90%). Both groups with GERD were more likely to experience greater severity of symptoms. We found the GERD Symptom Questionnaire useful in distinguishing infants and young children with symptomatic GERD from healthy children.

Eradication of Helicobacter pylori by 7-day triple-therapy regimens combining pantoprazole with clarithromycin, metronidazole, or amoxicillin in patients with peptic ulcer disease: results of two double-blind, randomized studies.

AIM: To compare the short-term (7-day) safety and efficacy of two triple-therapy regimens using pantoprazole with those of two dual-therapy regimens (one with pantoprazole and one without), for Helicobacter pylori eradication in patients with peptic ulcer disease. METHODS: H. pylori infection was identified by rapid urease (CLOtest), and confirmed by histology and culture. Patients were enrolled into one of two randomized, double-blind, multicenter, parallel-group studies. In study A, patients received oral pantoprazole 40 mg, clarithromycin 500 mg, and metronidazole 500 mg (PCM); pantoprazole, clarithromycin and amoxicillin 1000 mg (PCA); or pantoprazole and clarithromycin (PC). In study B, patients received PCM, PCA, PC, or clarithromycin and metronidazole without pantoprazole (CM). Treatments were given twice daily for 7 days. H. pylori status after therapy was assessed by histology and culture at 4 weeks after completing the course of study treatment. Modified intent-to-treat (MITT; each study: n = 424, n = 512) and per-protocol (PP; each study: n = 371, n = 454) populations were analyzed. The MITT population comprised all patients whose positive H. pylori status was confirmed by culture and histology; the PP population comprised patients who also complied with > or = 85% of study medication doses. RESULTS: A total of 1016 patients were enrolled. Cure rates among patients with clarithromycin-susceptible H. pylori strains were 82 and 86% for PCM, and 72 and 71% for PCA, in studies A and B, respectively. Cure rates among patients with metronidazole-susceptible H. pylori strains were 82 and 87% for PCM, and 71 and 69% for PCA, in studies A and B, respectively. The combined eradication rates observed with the PCM regimen were superior to those of all other regimens tested. Side-effects were infrequent and mild. CONCLUSIONS: PCM had the highest overall eradication rate in these two studies examining 7-day treatment regimens. All regimens were safe and well tolerated.