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Background: In clinical trials of medications to treat attention-deficit/hyperactivity disorder (ADHD) in children, effects on functional impairment have been less well-studied than changes in ADHD symptoms.Objective: Data regarding functional impairment were analyzed from a multicenter, double-blind, placebo-controlled study of guanfacine extended release (GXR) in children with ADHD, using the Weiss Functional Impairment Rating Scale-Parent Report (WFIRS-P). The correspondence of changes in WFIRS-P scores with symptomatic and global response to GXR treatment was also examined, with treatment response defined by scores on both the ADHD Rating Scale IV (ADHD-RS-IV) and the Clinical Global Impressions-Improvement Scale (CGI-I).Methods: In this 8-week, double-blind, placebo-controlled, dose optimization study at 47 sites across the USA and Canada, children aged 6-12 years with a diagnosis of ADHD [Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision criteria, and an ADHD-RS-IV score ≥28 and CGI-Severity of Illness Scale score ≥4 at baseline], were randomized 1:1:1 into three groups: GXR AM [GXR (1-4 mg/day) in the morning, placebo in the evening], GXR PM [placebo in the morning, GXR (1-4 mg/day) in the evening], or twice-daily placebo. Parents rated their children on the WFIRS-P at screening, baseline, the end of dose optimization, and at the final on-treatment assessment.Results: The efficacy population was composed of 333 subjects (GXR AM: n = 107; GXR PM: n = 114; placebo: n = 112). At the final on-treatment assessment, there were significant improvements from baseline in the placebo-adjusted difference in least-squares (LS) mean (95 % confidence interval) WFIRS-P Total scores for both GXR treatment groups combined [GXR all-active: -0.16 (-0.25, -0.07), effect size (ES) = 0.448, P <0.001] and separately [GXR AM: -0.15 (-0.26, -0.05), ES = 0.417, P = 0.004; GXR PM: -0.18 (-0.28, -0.07), ES = 0.478, P = 0.001]. Significant improvements in WFIRS-P domain scores for Family, Learning and School (including Academic Performance and Behavior in School), Social, and Risky Behavior were found for both GXR cohorts compared with placebo. However, the Life Skills and Self-Concept domain scores of the WFIRS-P did not improve with GXR treatment. Post hoc stratification by responder status revealed that significant (P <0.001) improvements in WFIRS-P Total and all domain scores were associated with symptomatic treatment response in the GXR all-active group.Conclusions: GXR treatment in children with ADHD was associated with reductions in WFIRS-P functional impairment scores compared with placebo, regardless of time of GXR administration. Changes in WFIRS-P scores were congruent with clinical response, as determined by both ADHD symptom reduction and CGI-I scores. CLINICALTRIALS.Gov Identifier: NCT00997984. [ABSTRACT FROM AUTHOR]

Background: MET (also known as hepatocyte growth factor receptor) signalling is a key driver of papillary renal cell carcinoma (PRCC). Given that no optimal therapy for metastatic PRCC exists, we aimed to compare an existing standard of care, sunitinib, with the MET kinase inhibitors cabozantinib, crizotinib, and savolitinib for treatment of patients with PRCC.Methods: We did a randomised, open-label, phase 2 trial done in 65 centres in the USA and Canada. Eligible patients were aged 18 years or older with metastatic PRCC who had received up to one previous therapy (excluding vascular endothelial growth factor-directed and MET-directed agents). Patients were randomly assigned to receive sunitinib, cabozantinib, crizotinib, or savolitinib, with stratification by receipt of previous therapy and PRCC subtype. All drug doses were administered orally: sunitinib 50 mg, 4 weeks on and 2 weeks off (dose reductions to 37·5 mg and 25 mg allowed); cabozantinib 60 mg daily (reductions to 40 mg and 20 mg allowed); crizotinib 250 mg twice daily (reductions to 200 mg twice daily and 250 mg once daily allowed); and savolitinib 600 mg daily (reductions to 400 mg and 200 mg allowed). Progression-free survival (PFS) was the primary endpoint. Analyses were done in an intention-to-treat population, with patients who did not receive protocol therapy excluded from safety analyses. This trial is registered with ClinicalTrials.gov, NCT02761057.Findings: Between April 5, 2016, and Dec 15, 2019, 152 patients were randomly assigned to one of four study groups. Five patients were identified as ineligible post-randomisation and were excluded from these analyses, resulting in 147 eligible patients. Assignment to the savolitinib (29 patients) and crizotinib (28 patients) groups was halted after a prespecified futility analysis; planned accrual was completed for both sunitinib (46 patients) and cabozantinib (44 patients) groups. PFS was longer in patients in the cabozantinib group (median 9·0 months, 95% CI 6-12) than in the sunitinib group (5·6 months, 3-7; hazard ratio for progression or death 0·60, 0·37-0·97, one-sided p=0·019). Response rate for cabozantinib was 23% versus 4% for sunitinib (two-sided p=0·010). Savolitinib and crizotinib did not improve PFS compared with sunitinib. Grade 3 or 4 adverse events occurred in 31 (69%) of 45 patients receiving sunitinib, 32 (74%) of 43 receiving cabozantinib, ten (37%) of 27 receiving crizotinib, and 11 (39%) of 28 receiving savolitinib; one grade 5 thromboembolic event was recorded in the cabozantinib group.Interpretation: Cabozantinib treatment resulted in significantly longer PFS compared with sunitinib in patients with metastatic PRCC.Funding: National Institutes of Health and National Cancer Institute. [ABSTRACT FROM AUTHOR]