Kathy Lampl

Test for Respiratory and Asthma Control in Kids (TRACK): A caregiver-completed questionnaire for preschool-aged children

BACKGROUND A validated questionnaire is needed to monitor respiratory control in preschool-aged children. OBJECTIVE We sought to develop and validate a caregiver-completed questionnaire that measures respiratory control in young children. METHODS A 33-item questionnaire that included asthma impairment and risk items was administered to 486 caregivers of children aged younger than 5 years with a current, recent, or past history of respiratory symptoms. Stepwise regression was used to select a subset of items with the greatest discriminant validity in relation to guidelines-defined asthma control in a random two-thirds development sample. Reliability, validity, and ability to screen for respiratory control problems were tested in development and validation samples (remaining one-third sample). RESULTS The content of the 5 items selected, the Test for Respiratory and Asthma Control in Kids (TRACK), included frequency of respiratory symptoms (wheeze, cough, shortness of breath), activity limitation, and nighttime awakenings in the past 4 weeks; rescue medication use in the past 3 months; and oral corticosteroid use in the previous year. Reliability was greater than 0.70 in both samples. ANOVA showed that mean scores differed significantly (P < .001) in the expected direction across both samples for 3 levels of guidelines-based respiratory control, physician-recommended change in therapy, and symptom status. In the development and validation samples, screening analyses revealed areas under the receiver operating characteristic curve of 0.88 and 0.82, respectively; control status was correctly classified in 81% and 78% of cases. CONCLUSION TRACK is a valid, easy-to-administer, caregiver-completed questionnaire of respiratory control in preschool-aged children with symptoms consistent with asthma.

A phase III, multicenter, randomized, double-blind, placebo-controlled, parallel-group study of 2 dosing regimens of fostamatinib in patients with rheumatoid arthritis with an inadequate response to a tumor necrosis factor-α antagonist

Objective. Our 24-week study (NCT01197755; OSKIRA-3) compared the efficacy and safety of fostamatinib versus placebo in patients taking background methotrexate treatment with active rheumatoid arthritis (RA) and an inadequate response to a single tumor necrosis factor-α antagonist. Methods. Adult patients were randomized (1:1:1) to fostamatinib [100 mg bid for 24 weeks (n = 105; Group A)], or 100 mg bid for 4 weeks, then 150 mg qd (n = 108; Group B), or to placebo (n = 110; Group C) for 24 weeks. Nonresponders at Week 12 could enter a longterm extension study. The primary endpoint was the proportion of patients achieving an American College of Rheumatology 20% (ACR20) response at Week 24. Results. Baseline characteristics were well balanced. Significantly more patients in fostamatinib Group A (36.2%; p = 0.004), but not B (27.8%; p = 0.168), achieved ACR20 at Week 24 versus placebo (21.1%). Frequently reported adverse events were diarrhea, hypertension, and headache. Elevated blood pressure (≥ 140/90 mm Hg) at ≥ 1 visit was observed in 46.7%, 51.9%, and 26.6% of patients, respectively. There were 2 deaths in the study, 1 in Group B and 1 in the placebo group. Conclusion. Fostamatinib 100 mg bid, but not fostamatinib 100 mg bid for 4 weeks then 150 mg qd, achieved statistical improvements in ACR20 at 24 weeks versus placebo. Because of efficacy and safety results from the phase III clinical program, the companies developing fostamatinib have decided not to study it further in RA at this time.

Long-term safety and asthma control measures with a budesonide/formoterol pressurized metered-dose inhaler in African American asthmatic patients: A randomized controlled trial

BACKGROUND Information surrounding the long-term safety of combination inhaled corticosteroid/long-acting β(2)-adrenergic agonist medications in African American asthmatic patients is limited. OBJECTIVE We sought to assess safety and asthma control with a budesonide/formoterol pressurized metered-dose inhaler (pMDI) versus budesonide over 1 year in African American patients. METHODS This 52-week, randomized, double-blind, parallel-group, multicenter, phase 3B safety study (NCT00419952) was conducted in 742 self-reported African American patients 12 years or older with moderate-to-severe asthma previously receiving medium- to high-dose inhaled corticosteroids. After 2 weeks using a 320 μg twice-daily budesonide pMDI, patients were randomized 1:1 to 320/9 μg twice-daily budesonide/formoterol pMDI or 320 μg twice-daily budesonide pMDI. RESULTS Both treatments were well tolerated. Asthma exacerbation incidence and rate (per patient-treatment year) were lower with budesonide/formoterol versus budesonide (incidence, 7.7% vs 14.0% [P= .006]; rate ratio, 0.615 [P= .002]). Time to first asthma exacerbation was longer (P= .018) with budesonide/formoterol versus budesonide. The most common adverse events, regardless of study drug relationship, were headache (9.5% and 7.7%), nasopharyngitis (6.9% and 8.0%), sinusitis (4.0% and 6.3%), and viral upper respiratory tract infection (5.8% and 4.4%) for budesonide/formoterol and budesonide, respectively. Serious adverse events occurred in 12 and 15 patients, respectively; none were considered drug related. No substantial or unexpected patterns of abnormalities were observed in laboratory, electrocardiographic, or Holter monitoring assessments. Hospitalization caused by asthma exacerbation occurred in 0 and 4 patients in the budesonide/formoterol and budesonide groups, respectively. Pulmonary function and asthma control measures generally favored budesonide/formoterol. CONCLUSIONS In this population budesonide/formoterol pMDI was well tolerated over 12 months, with a safety profile similar to that of budesonide; the asthma exacerbation rate was reduced by 38.5% versus budesonide.

Methodological Challenges When Comparing Demographic and Clinical Characteristics of International Observational Registries.

Comparisons of data from different registries can be helpful in understanding variations in many aspects of rheumatoid arthritis (RA). The study aim was to assess and improve the comparability of demographic, clinical, and comorbidity data from 5 international RA registries.

Using epidemiological registry data to provide background rates as context for adverse events in a rheumatoid arthritis drug development program: a coordinated approach†

Observational studies can provide context for adverse events observed in clinical trials, especially for infrequent events or long‐term risks. We developed methods to improve safety contextualization for a rheumatoid arthritis drug development program through coordinated analyses of multiple registries.

Bronchodilator effect of single-dose formoterol administered by pressurized metered-dose inhaler in children with asthma aged 6 to <12 years receiving budesonide.

Dose-response of formoterol via pressurized metered-dose inhaler (pMDI) has not been determined in asthmatic pediatric patients aged 6 to <12 years. This study was designed to assess the bronchodilating dose-response of three formoterol pMDI doses in children with stable asthma aged 6 to <12 years receiving twice-daily (b.i.d.) budesonide 160 micrograms. A U.S., multicenter, five-way crossover study compared single doses of formoterol, a long-acting beta-agonist, via pMDI (2.25, 4.5, and 9 micrograms) or dry powder inhaler (12 micrograms; active comparator) and placebo, with a 3- to 14-day washout period between doses. Budesonide pMDI 160 micrograms, an inhaled corticosteroid, was given b.i.d. throughout the study. Fifty-four pediatric patients (mean age, 9.2 years; mean asthma history, 6.1 years) were randomized. All formoterol doses showed significantly higher average 12-hour forced expiratory volume in 1 second (FEV1; area under the curve) versus placebo (primary efficacy). Formoterol pMDI 4.5 and 9 micrograms showed significantly greater average 12-hour FEV1 than formoterol 2.25 micrograms (p = 0.0007 and p = 0.0001, respectively). Formoterol also resulted in significant improvement in maximum FEV1 during the 12-hour treatment period (secondary efficacy) with formoterol 4.5-, 9-, and 12-microgram doses versus placebo and the formoterol 2.25-microgram dose. Bronchodilation was not maintained during the 12-hour dosing interval with formoterol 2.25 micrograms. No serious adverse events were reported. Formoterol pMDI showed generally dose-proportional pharmacokinetics to 9 micrograms, as determined by urinary excretion. Single doses of formoterol pMDI showed a dose-response, with formoterol 9 micrograms exhibiting a maximum response, in pediatric patients aged 6 to <12 years with persistent stable asthma maintained on b.i.d. budesonide pMDI 160 micrograms. Clinical trial NCT01136655, www.clinicaltrials.gov.

Review of Routine Laboratory Monitoring for Patients with Rheumatoid Arthritis Receiving Biologic or Nonbiologic DMARDs

Safety concerns associated with many drugs indicated for the treatment of rheumatoid arthritis (RA) can be attenuated by the early identification of toxicity through routine laboratory monitoring; however, a comprehensive review of the recommended monitoring guidelines for the different available RA therapies is currently unavailable. The aim of this review is to summarize the current guidelines for laboratory monitoring in patients with RA and to provide an overview of the laboratory abnormality profiles associated with each drug indicated for RA. Recommendations for the frequency of laboratory monitoring of serum lipids, liver transaminases, serum creatinine, neutrophil counts, and platelet counts in patients with RA were compiled from a literature search for published recommendations and guidelines as well as the prescribing information for each drug. Laboratory abnormality profiles for each drug were compiled from the prescribing information for each drug and a literature search including meta-analyses and primary clinical trials data.

THU0138 The Corrona International Rheumatoid Arthritis Registry: Variations in Disease Activity and Management Across Participating Regions

Background To date, there is no multinational Rheumatoid Arthritis (RA) registry uniformly collecting longitudinal data. The CORRONA International (CI) registry was developed to address this need. Objectives To explore variations in RA disease (dx) activity and drug utilization across regions participating in CI RA registry and the US CORRONA RA registry. Methods The CI registry, launched in September 2011, is a multi-center, longitudinal, observational registry collecting data on demographics, lifestyle characteristics, anthropometry, medication exposures, adverse events and toxicities from rheumatologists and RA patients (pts) at regular clinical encounters. Adult RA pts have been enrolled in 10 countries in 3 regions [Eastern Europe: Poland, Czech Republic, Hungary, Romania, Russia, Ukraine; Latin America: Mexico, Brazil, Argentina; Asia: India]. We present baseline descriptive data including: variations in biologic and DMARD utilization, dx activity and functionality across the regions participating in both registries. Results As of Nov 2012, 4042 patients had been enrolled in CI. Table 1 shows variations in dx characteristics among the CI regions and the USA. In general, dx activity is higher but functionality and biologic drug utilization is lower in CI regions compared to USA. Biologics use is still very rare in India. Conclusions The CI registry reveals differences in the management of RA across different global regions. The ongoing recruitment and follow-up of more pts will enable association studies between therapeutic variations and disease outcomes. Acknowledgements Funding for this study was provided by CORRONA (study sponsor), from a development and subscription agreement/contract with AstraZeneca. Disclosure of Interest D. Pappas Employee of: Columbia University, Paid instructor for: Novartis, K. Lampl Employee of: AstraZeneca, J. Kremer Shareholder of: CORRONA, Inc., Employee of: CORRONA, Inc., F. Nyberg Employee of: AstraZeneca, A. Gibofsky Consultant for: AstraZeneca, M. Ho Employee of: AstraZeneca, L. Horne Shareholder of: AstraZeneca, Employee of: AstraZeneca, K. Saunders Employee of: CORRONA, Inc., A. Onofrei Employee of: University of Massachusetts, J. Greenberg Shareholder of: CORRONA, Inc., Consultant for: AstraZeneca, CORRONA, Novartis, Pfizer

Prevalence of cardiovascular disease and major risk factors in patients with rheumatoid arthritis: a multinational cross-sectional study

To compare the prevalence of cardiovascular disease (CVD) and major CVD risk factors among rheumatoid arthritis (RA) patients enrolled in a large US and multinational registry. We compared CVD and CVD risk factor prevalence from 11 countries enrolled in the CORRONA US and CORRONA International registries; patients from the 10 ex-US participating countries were grouped by region (Eastern Europe, Latin America, and India). Unadjusted summary data were presented for demographics and disease characteristics; comparisons for prevalence of CVD risk factors and CVD were age/gender standardized to the age/gender distribution of the US enrolled patients. Overall, 25,987 patients were included in this analysis. Compared to patients from the ex-US regions, US participants had longer disease duration and lower disease activity, yet were more likely to receive a biologic agent. Additionally, CORRONA US participants had the highest body mass index (BMI). Enrolled patients in India had the lowest BMI, were more rarely smokers, and had a low prevalence of hyperlipidemia, hypertension, and prior CVD compared to the US and other ex-US regions. Participants from Eastern Europe had a higher prevalence of hypertension and hyperlipidemia and highest prevalence of all manifestations of CVD. Differences in the prevalence of both CVD and major CVD risk factors were observed across the four regions investigated. Observed differences may be influenced by variations in both non-modifiable/modifiable characteristics of patient populations, and may contribute to heterogeneity on the observed safety of investigational and approved therapies in studies involving RA patients from different origins.

FRI0253 Patient-reported outcomes in patients with rheumatoid arthritis treated with subcutaneous tocilizumab compared with placebo or intravenous tocilizumab in combination with csdmards

Background Two previous randomized, controlled trials (RCTs), BREVACTA and SUMMACTA, showed subcutaneous tocilizumab (TCZ-SC) was superior to placebo (PBO) and comparable to intravenous TCZ (TCZ-IV) in combination with csDMARDs for improving RA disease activity.1,2 Objectives To compare the efficacy of TCZ-SC with PBO or TCZ-IV + csDMARDs for improvement in patient-reported outcomes (PROs) in 2 RCT populations. Methods Both RCTs enrolled patients (pts) with inadequate responses to DMARDs; up to 20% had inadequate responses to tumor necrosis factor inhibitors. In BREVACTA, pts received blinded TCZ-SC 162 mg or PBO every 2 weeks (q2w) + csDMARDs for 24 weeks. In SUMMACTA, pts received TCZ-SC 162 mg weekly or TCZ-IV 8 mg/kg q4w + csDMARDs for the 24-week double-blind period. PROs, assessed at 12 weeks (prior to rescue) in BREVACTA and 24 weeks in SUMMACTA, included patient global assessment (PtGA; visual analog score [VAS], 0–100 mm), pain (VAS), Health Assessment Questionnaire Disability Index (HAQ-DI, 0–3) and Short Form-36 (SF-36) physical and mental component summary (PCS, MCS: 0–50) and domain (0–100) scores. The proportions of pts reporting scores ≥ minimum clinically important differences (MCID) and ≥ age/gender-matched normative values were assessed for each treatment group. Results Baseline PRO scores were mostly comparable between treatment groups in each study and between study populations. In BREVACTA, significantly more pts who received TCZ-SC reported scores ≥ MCID for all PROs at week 12 compared with PBO (54% to 73% vs 42% to 55%, respectively; number needed to treat [NNT], 5.2 to 13.0). Compared with 1% to 20% at baseline, 8% to 34% of pts who received TCZ-SC and 4% to 25% of PBO pts reported scores ≥ normative values in all PROs at week 12 (Table). In SUMMACTA, similar proportions of pts who received TCZ-SC and TCZ-IV reported scores ≥ MCID in all PROs at week 24 (61% to 84% vs 64% to 84%, respectively). The proportion of patients who reported scores ≥ normative values was comparable between the TCZ-SC and TCZ-IV groups across all PROs; compared with 0.2% to 23% at baseline, 14% to 41% of pts who received TCZ-SC and 15% to 42% of pts who received TCZ-IV reported scores ≥ normative values at week 24 (Table). Conclusions In BREVACTA, TCZ-SC + csDMARDs resulted in significantly greater improvements across all PROs and significantly more pts reporting scores ≥ MCID at week 12 compared with PBO. Similarly, more pts receiving TCZ-SC reported scores ≥ normative values at week 12 compared with PBO, despite few pts with such scores at baseline. Responses were similar between pts treated with TCZ-SC and TCZ-IV + csDMARDs in SUMMACTA at week 24. These data show TCZ treatment resulted in clinically meaningful improvements in PROs and indicate that attainment of normative scores is a realistic goal in treatment of pts with active RA. References Kivitz A, et al. Arthritis Care Res (Hoboken). 2014;66:1653–61. Burmester G, et al. Ann Rheum Dis. 2014;73:69–74. Acknowledgements This study was funded by F. Hoffmann-La Roche/Genentech. Disclosure of Interest V. Strand Consultant for: Abbvie; Amgen; AstraZeneca; Biogen Idec; Boehringer Ingelheim; Celltrion; Crescendo; Genentech/Roche; GlaxoSmithKline; Janssen; Lilly; Merck; Novartis; Pfizer; Regeneron; Samsung; Sanofi; UCB, K. Lampl Employee of: Genentech, Inc, C. Birchwood Employee of: Genentech, Inc, J. Pei Employee of: Genentech, Inc, K. Tuckwell Shareholder of: Roche, Employee of: Roche, R. Finch Shareholder of: Roche, Employee of: Roche, A. Kivitz Consultant for: Genentech; Novartis; Pfizer; Sanofi-Regeneron; UCB, G. Burmester Grant/research support from: Roche, Consultant for: Roche