Canagliflozin and Cardiovascular and Renal Outcomes in Type 2 Diabetes Mellitus and Chronic Kidney Disease in Primary and Secondary Cardiovascular Prevention Groups Results From the Randomized CREDENCE Trial

Sources of Funding This study is sponsored by Janssen Research & Development, LLC, which funded the trial. The sponsor was involved in the study design, the writing of the report, and the decision to submit the article for publication. Canagliflozin has been developed by Janssen Research & Development, LLC, in collaboration with Mitsubishi Tanabe Pharma Corporation. Acknowledgments The authors thank all participants, investigators, and trial teams for their participation in the trial and the following people for their contributions to the statistical monitoring and analyses and the protocol development, safety monitoring, and operational implementation over the duration of the trial: Maria Ali, Jim Baldassarre, Dainius Balis, William Canovatchel, Jun Chen, Pei-Ling Chu, Trokon Cooke, Jag Craig, Jacki Danyluk, Mehul Desai, Lyndal Hones, Alan Jenkins, Mary Kavalam, Cha-Chi Lo, Xinchao Luo, Gary Meininger, Rich Oh, Rose Qiu, Nicole Schmitt, Danielle Siebenkaess, Roger Simpson, Anna Temu, Payal Thakkar, Michele Wells, and Renata Yong. The Steering Committee designed the study in conjunction with the sponsor. Dr Mahaffey wrote the first draft of the paper, had full access to the study design information, and had final responsibility for the decision to submit for publication. All authors provided input into subsequent drafts and approved the final version for submission. Editorial assistance for manuscript preparation was provided by Alaina Mitsch, PhD, and Kimberly Dittmar, PhD, of MedErgy, and was funded by Janssen Global Services, LLC. All authors reviewed and approved the manuscript.Peer reviewe

Relationship Between Sleep and Behavior in Autism Spectrum Disorder: Exploring the Impact of Sleep Variability.

Objective:The relationship between sleep (caregiver-reported and actigraphy-measured) and other caregiver-reported behaviors in children and adults with autism spectrum disorder (ASD) was examined, including the use of machine learning to identify sleep variables important in predicting anxiety in ASD. Methods:Caregivers of ASD (n = 144) and typically developing (TD) (n = 41) participants reported on sleep and other behaviors. ASD participants wore an actigraphy device at nighttime during an 8 or 10-week non-interventional study. Mean and variability of actigraphy measures for ASD participants in the week preceding midpoint and endpoint were calculated and compared with caregiver-reported and clinician-reported symptoms using a mixed effects model. An elastic-net model was developed to examine which sleep measures may drive prediction of anxiety. Results:Prevalence of caregiver-reported sleep difficulties in ASD was approximately 70% and correlated significantly (p < 0.05) with sleep efficiency measured by actigraphy. Mean and variability of actigraphy measures like sleep efficiency and number of awakenings were related significantly (p < 0.05) to ASD symptom severity, hyperactivity and anxiety. In the elastic net model, caregiver-reported sleep, and variability of sleep efficiency and awakenings were amongst the important predictors of anxiety. Conclusion:Caregivers report problems with sleep in the majority of children and adults with ASD. Reported problems and actigraphy measures of sleep, particularly variability, are related to parent reported behaviors. Measuring variability in sleep may prove useful in understanding the relationship between sleep problems and behavior in individuals with ASD. These findings may have implications for both intervention and monitoring outcomes in ASD

Ibrutinib versus temsirolimus in patients with relapsed or refractory mantle-cell lymphoma: an international, randomised, open-label, phase study

Background: Mantle-cell lymphoma is an aggressive B-cell lymphoma with a poor prognosis. Both ibrutinib and temsirolimus have shown single-agent activity in patients with relapsed or refractory mantle-cell lymphoma. We undertook a phase 3 study to assess the efficacy and safety of ibrutinib versus temsirolimus in relapsed or refractory mantle-cell lymphoma. Methods: This randomised, open-label, multicentre, phase 3 clinical trial enrolled patients with relapsed or refractory mantle-cell lymphoma confirmed by central pathology in 21 countries who had received one or more rituximab-containing treatments. Patients were stratified by previous therapy and simplified mantle-cell lymphoma international prognostic index score, and were randomly assigned with a computer-generated randomisation schedule to receive daily oral ibrutinib 560 mg or intravenous temsirolimus (175 mg on days 1, 8, and 15 of cycle 1; 75 mg on days 1, 8, and 15 of subsequent 21-day cycles). Randomisation was balanced by using randomly permuted blocks. The primary efficacy endpoint was progression-free survival assessed by a masked independent review committee with the primary hypothesis that ibrutinib compared with temsirolimus significantly improves progression-free survival. The analysis followed the intention-to-treat principle. The trial is ongoing and is registered with ClinicalTrials.gov (number NCT01646021) and with the EU Clinical Trials Register, EudraCT (number 2012-000601-74). Findings: Between Dec 10, 2012, and Nov 26, 2013, 280 patients were randomised to ibrutinib (n=139) or temsirolimus (n=141). Primary efficacy analysis showed significant improvement in progression-free survival (p<0.0001) for patients treated with ibrutinib versus temsirolimus (hazard ratio 0.43 [95% CI 0.32-0.58]; median progression-free survival 14.6 months [95% CI 10.4-not estimable] vs 6.2 months [4.2-7.9], respectively). Ibrutinib was better tolerated than temsirolimus, with grade 3 or higher treatment-emergent adverse events reported for 94 (68%) versus 121 (87%) patients, and fewer discontinuations of study medication due to adverse events for ibrutinib versus temsirolimus (9 [6%] vs 36 [26%]). Interpretation: Ibrutinib treatment resulted in significant improvement in progression-free survival and better tolerability versus temsirolimus in patients with relapsed or refractory mantle-cell lymphoma. These data lend further support to the positive benefit-risk ratio for ibrutinib in relapsed or refractory mantle-cell lymphoma

Markers of inflammation and bone remodelling associated with improvement in clinical response measures in psoriatic arthritis patients treated with golimumab

&lt;p&gt;Objective To determine serum biomarker associations with clinical response to golimumab treatment in patients with psoriatic arthritis (PsA).&lt;/p&gt; &lt;p&gt;Methods GO–REVEAL was a randomised, placebo-controlled study of golimumab in patients with active PsA. Samples were collected from 100 patients at baseline, week 4 and week 14, and analysed for serum-based biomarkers and protein profiling (total 92 markers); data were correlated with clinical measures at week 14.&lt;/p&gt; &lt;p&gt;Results Serum levels of a subset of proteins (apolipoprotein C III, ENRAGE, IL-16, myeloperoxidase, vascular endothelial growth factor, pyridinoline, matrix metalloproteinase 3, C-reactive protein (CRP), carcinoembryonic antigen, intercellular adhesion molecule 1 and macrophage inflammatory protein 1α) at baseline or week 4 were strongly associated with American College of Rheumatology 20% improvement (ACR20) response and/or disease activity score in 28 joints (DAS28) at week 14. A smaller subset of proteins was significantly associated with a 75% improvement in the psoriasis area and severity index score (PASI75) at week 14, (adiponectin, apolipoprotein CIII, serum glutamic oxaloacetic transaminase, and tumour necrosis factor α). Subsets of proteins were identified as potentially predictive of clinical response for each of the clinical measures, and the power of these biomarker panels to predict clinical response to golimumab treatment was stronger than for CRP alone.&lt;/p&gt; &lt;p&gt;Conclusions This analysis provides insight into several panels of markers that may have utility in identifying PsA patients likely to have ACR20, DAS28, or PASI75 responses following golimumab treatment.&lt;/p&gt

Clinical efficacy, radiographic and safety findings through 2 years of golimumab treatment in patients with active psoriatic arthritis: results from a long-term extension of the randomised, placebo-controlled GO-REVEAL study

Objectives: To assess long-term golimumab efficacy/safety in patients with active psoriatic arthritis (PsA).&lt;p&gt;&lt;/p&gt; Methods Adult PsA patients (&#8805;3 swollen, &#8805;3 tender joints, active psoriasis) were randomly assigned to subcutaneous injections of placebo, golimumab 50 mg or 100 mg every 4 weeks (q4wks) through week 20. All patients received golimumab 50 or 100 mg beginning week 24. Findings through 2 years are reported. Efficacy evaluations included &#8805;20% improvement in American College of Rheumatology (ACR20) response, good/moderate response in Disease Activity Scores incorporating 28 joints and C-reactive protein (DAS28-CRP), &#8805;75% improvement in Psoriasis Area and Severity Index (PASI75) and changes in PsA-modified Sharp/van der Heijde scores (SHS).&lt;p&gt;&lt;/p&gt; Results: Golimumab treatment through 2 years was effective in maintaining clinical response (response rates: ACR20 63%–70%, DAS28-CRP 77%–86%, PASI75 56%–72%) and inhibiting radiographic progression (mean change in PsA-modified SHS in golimumab-treated patients: −0.36), with no clear difference between doses. No new safety signals were identified through 2 years. With the study's tuberculosis screening and prophylactic measures, no patient developed active tuberculosis through 2 years.&lt;p&gt;&lt;/p&gt; Conclusions: Golimumab 50 and 100 mg for up to 2 years yielded sustained clinical and radiographic efficacy when administered to patients with active PsA. Increasing the golimumab dose from 50 to 100 mg q4wks added limited benefit. Golimumab safety through up to 2 years was consistent with other antitumour necrosis factor α agents used to treat PsA. Treatment of patients with latent tuberculosis identified at baseline appeared to be effective in inhibiting the development of active tuberculosis.&lt;p&gt;&lt;/p&gt

Patient-reported outcome assessment of inflammatory arthritis patient experience with intravenously administered biologic therapy

Objective: To evaluate patient perspectives regarding utilization of intravenous (IV) therapy for inflammatory arthritis (IA). Methods: This was a single-center, non-interventional, patient questionnaire-based study of adult IA patients currently receiving IV biologics. At a single visit, patients completed the questionnaire comprising 30 questions centered on their experience receiving an intravenously administered therapy to treat their IA. The questionnaire included questions on patient demographics, disease characteristics, and previous biologic treatment for IA (subcutaneous [SC] and IV). Patients rated their level of agreement with statements regarding satisfaction with current IV biologic therapy and potential advantages and disadvantages of IV biologic therapy using a 5-point Likert scale (1= strongly disagree, 5= strongly agree). Results: One hundred patients were enrolled and completed the survey; 66% were female and the mean age was 58 years. Before IV treatment, 97% of patients received information regarding therapy options. Ninety patients ranked their satisfaction with current IV therapy as 4 or 5. The proportion of patients with an “extremely favorable” perception of IV therapy increased from 33% to 71% following initiation of their current medication. Thirty-one patients had previously received SC therapies to treat their IA. Conclusion: These results demonstrated an overall favorable perception of IV therapy among this patient population. Patients previously treated with SC therapy also had a positive shift in the perception of IV therapy after initiating IV therapy. Patients’ perception and preference for treatment options should be highly considered by the treating physician during or as part of a shared decision-making process. © 2017 Gaylis et al

Ustekinumab treatment and improvement of physical function and health‐related quality of life in patients with psoriatic arthritis

Objective: Examine ustekinumab effects on patient-reported outcomes (PROs) in PSUMMIT-1/PSUMMIT-2 patients with active psoriatic arthritis (PsA) who were methotrexate (MTX)-naïve, MTX-experienced, or anti-tumor necrosis factor (TNF)-experienced. Methods: Patients in the Phase 3, PSUMMIT 1 (n=615) and PSUMMIT 2 (n=312) studies randomly (1:1:1) received placebo, ustekinumab 45 mg, or ustekinumab 90 mg subcutaneous injections at wk0/wk4/wk16/wk28/wk40/wk52. PROs (Health Assessment Questionnaire-Disability Index [HAQ-DI]; Dermatology Life Quality index [DLQI]; 36-item short-form health survey physical and mental component summary [SF-36 PCS/MCS] scores; patient assessments of pain and disease activity; impact of disease on productivity) were assessed at wk0/wk24/wk52. In these post-hoc analyses, outcomes were compared between the ustekinumab and placebo groups for three mutually-exclusive antecedent-exposure populations from the combined studies: MTX/anti-TNF naïve (placebo, n=56; 45 mg, n=58; 90 mg, n=66), MTX-experienced, bio-naive (placebo, n=192; 45 mg, n=190; 90 mg, n=185), and anti-TNF experienced with or without MTX (placebo, n=62; 45 mg, n=60, 90 mg, n=58). Results: At wk24, mean improvements from baseline in HAQ-DI, DLQI, and SF-36 PCS scores were significantly greater in both ustekinumab groups versus placebo across antecedent-exposure groups. Greater proportions of ustekinumab- than placebo-treated patients (all p&lt;0.05) had clinically meaningful improvements in HAQ-DI (≥0.3), DLQI (≥5), and SF-36 (≥5) scores at wk24, irrespective of drug exposure. Improvements in pain, disease activity, and impact of disease on productivity were similar, and benefits were maintained through wk52. Conclusions: Significant improvements in PROs with ustekinumab vs. placebo were observed in three antecedent-exposure populations of PsA patients, including those with prior MTX and anti-TNF use