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Lenvatinib plus either pembrolizumab or everolimus was compared with sunitinib as first-line therapy for advanced renal cell cancer. Progression-free survival was significantly longer with lenvatinib plus pembrolizumab than with sunitinib. Lenvatinib plus everolimus was also more effective than sunitinib, but the difference was smaller.

Closed-loop systems link continuous glucose measurements to insulin delivery. We aimed to establish whether closed-loop insulin delivery could control overnight blood glucose in young people. We undertook three randomised crossover studies in 19 patients aged 5–18 years with type 1 diabetes of duration 6·4 years (SD 4·0). We compared standard continuous subcutaneous insulin infusion and closed-loop delivery (n=13; APCam01); closed-loop delivery after rapidly and slowly absorbed meals (n=7; APCam02); and closed-loop delivery and standard treatment after exercise (n=10; APCam03). Allocation was by computer-generated random code. Participants were masked to plasma and sensor glucose. In APCam01, investigators were masked to plasma glucose. During closed-loop nights, glucose measurements were fed every 15 min into a control algorithm calculating rate of insulin infusion, and a nurse adjusted the insulin pump. During control nights, patients' standard pump settings were applied. Primary outcomes were time for which plasma glucose concentration was 3·91–8·00 mmol/L or 3·90 mmol/L or lower. Analysis was per protocol. This trial is registered, number ISRCTN18155883. 17 patients were studied for 33 closed-loop and 21 continuous infusion nights. Primary outcomes did not differ significantly between treatment groups in APCam01 (12 analysed; target range, median 52% [IQR 43–83] closed loop vs 39% [15–51] standard treatment, p=0·06; ≤3·90 mmol/L, 1% [0–7] vs 2% [0–41], p=0·13), APCam02 (six analysed; target range, rapidly 53% [48–57] vs slowly absorbed meal 55% [37–64], p=0·97; ≤3·90 mmol/L, 0% [0–4] vs 0% [0–0], p=0·16]), and APCam03 (nine analysed; target range 78% [60–92] closed loop vs 43% [25–65] control, p=0·0245, not significant at corrected level; ≤3·90 mmol/L, 10% [2–15] vs 6% [0–44], p=0·27). A secondary analysis of pooled data documented increased time in the target range (60% [51–88] vs 40% [18–61]; p=0·0022) and reduced time for which glucose concentrations were 3·90 mmol/L or lower (2·1% (0·0–10·0) vs 4·1% (0·0–42·0); p=0·0304). No events with plasma glucose concentration lower than 3·0 mmol/L were recorded during closed-loop delivery, compared with nine events during standard treatment. Closed-loop systems could reduce risk of nocturnal hypoglycaemia in children and adolescents with type 1 diabetes. Juvenile Diabetes Research Foundation; European Foundation for Study of Diabetes; Medical Research Council Centre for Obesity and Related Metabolic Diseases; National Institute for Health Research Cambridge Biomedical Research Centre.

OBJECTIVE: Continuous glucose monitoring (CGM) has been demonstrated to improve glycemic control in adults with type 1 diabetes but less so in children. We designed a study to assess CGM benefit in young children aged 4 to 9 years with type 1 diabetes. RESEARCH DESIGN AND METHODS: After a run-in phase, 146 children with type 1 diabetes (mean age 7.5 ± 1.7 years, 64% on pumps, median diabetes duration 3.5 years) were randomly assigned to CGM or to usual care. The primary outcome was reduction in HbA1c at 26 weeks by ≥0.5% without the occurrence of severe hypoglycemia. RESULTS: The primary outcome was achieved by 19% in the CGM group and 28% in the control group (P = 0.17). Mean change in HbA1c was –0.1% in each group (P = 0.79). Severe hypoglycemia rates were similarly low in both groups. CGM wear decreased over time, with only 41% averaging at least 6 days/week at 26 weeks. There was no correlation between CGM use and change in HbA1c (rs = –0.09, P = 0.44). CGM wear was well tolerated, and parental satisfaction with CGM was high. However, parental fear of hypoglycemia was not reduced. CONCLUSIONS: CGM in 4- to 9-year-olds did not improve glycemic control despite a high degree of parental satisfaction with CGM. We postulate that this finding may be related in part to limited use of the CGM glucose data in day-to-day management and to an unremitting fear of hypoglycemia. Overcoming the barriers that prevent integration of these critical glucose data into day-to-day management remains a challenge.

ABSTRACT E7777 is a therapeutic recombinant fusion protein comprised of diphtheria toxin fragments and human interleukin‐2 (IL‐2). Treatment with E7777 generates anti‐drug antibodies (ADA). E7777‐G000‐302 assessed the efficacy and safety of E7777 in patients with relapsed or refractory cutaneous T‐cell lymphoma (CTCL). Here, we describe the association between E7777 (at 9 μg/kg) and ADAs, and its effect on pharmacokinetics (PK), efficacy, and safety. Of 91 patients with immunogenicity results at baseline, 78.0% and 5.5% had preexisting anti‐E7777 (E‐ADAs) and anti‐IL‐2 antibodies (I‐ADAs), respectively. The prevalence of E‐ADAs and I‐ADAs peaked at C3D1 (median titer 650,175) and C8D1 (median titer 32,805), respectively. However, I‐ADA fold increases (1312‐fold) were higher than E‐ADA increases (181‐fold). ADAs' effect on PK was assessed after treatment. E7777 reached Cmax at 60 min after infusion, with clearance of 44.6 mL/min at C1D1 and 133 mL/min at C5D1. Cmax and AUC(0–t) decreased by 60% and 84%, respectively, at C5D1 compared with C1D1. Of patients in the safety analysis set (n = 84) evaluated for treatment‐emergent (TE) ADAs, 92.9% were considered TE E‐ADA positive and 82.1% were TE I‐ADA positive. The objective response rate was 39.0% in TE E‐ADA‐positive patients and 42.6% in TE I‐ADA‐positive patients. Serious TE adverse events were reported by 32.1% of TE E‐ADA‐positive patients, 29.0% of TE I‐ADA‐positive patients, 100% of E‐ADA‐negative patients, and 73.3% of I‐ADA‐negative patients. These results indicate that the presence of ADAs decreased E7777 exposure over time but did not adversely impact efficacy and safety in patients with CTCL.

RESEARCH DESIGN AND METHODS- Institutional review boards at each of the Diabetes Research in Children Network (DirecNet) centers approved the study protocol and consent/ assent forms.

OBJECTIVE: To determine the individual persistence of the relationship between mean sensor glucose (MG) concentrations and hemoglobin A₁c (A1C) from the Juvenile Diabetes Research Foundation Continuous Glucose Monitoring (CGM) Randomized Trial. RESEARCH DESIGN AND METHODS: MG was calculated using CGM data for 3 months before A1C measurements at 3, 6, 9, and 12 months for the CGM group and at 9 and 12 months for the control group. An MG-to-A1C ratio was included in analysis for subjects who averaged ≥4 days/week of CGM use. RESULTS: Spearman correlations of the MG-to-A1C ratio between consecutive visits 3 months apart ranged from 0.70 to 0.79. The correlations for children and youth were slightly smaller than those for adults. No meaningful differences were observed by device type or change in A1C. CONCLUSIONS: Individual variations in the rate of hemoglobin glycation are persistent and contribute to the inaccuracy in estimating MGs calculated from A1C levels.

OBJECTIVE: To investigate if oral glutamine ameliorates exercise and postexercise nighttime hypoglycemia in type 1 diabetic adolescents. RESEARCH DESIGN AND METHODS: Ten adolescents (15.2 ± 1.4 years [SD], A1C 6.9 ± 0.9%) on insulin pumps were studied. The subjects were randomized to receive a glutamine or placebo drink pre-exercise and at bedtime (0.25 g/kg/dose). A 3:00 P.M. exercise session consisted of four 15-min treadmill/5-min rest cycles. Pre-exercise blood glucose was 140-150 mg/dl and was monitored throughout the night. Studies were randomized crossover over 3 weeks. RESULTS: Blood glucose levels dropped comparably (52%) during exercise on both days. However, the overnight number of hypoglycemic events was higher on glutamine than placebo ([less-than or equal to]70 mg/dl, P = 0.03 and [less-than or equal to]60, P = 0.05). The cumulative probability of nighttime hypoglycemia was increased on glutamine days (80%) versus placebo days (50%) (P = 0.02). CONCLUSIONS: Glutamine increased the cumulative probability of postexercise overnight hypoglycemia compared with placebo in adolescents with type 1 diabetes. Whether glutamine may enhance insulin sensitivity postexercise requires further study in type 1 diabetes.

To determine whether continuous glucose monitoring (CGM) is effective in the management of type 1 diabetes when implemented in a manner that more closely approximates clinical practice. After completion of a 6-month randomized controlled trial (RCT) evaluating CGM in children, adolescents, and adults with type 1 diabetes, CGM was initiated in the trial's control group with less intensive training and follow-up than was included in the RCT. Subjects had an outpatient training session, two follow-up phone calls, and outpatient visits at 1, 4, 13, and 26 weeks. For subjects with baseline A1C > or =7.0%, the primary outcome was change in A1C at 6 months. CGM use decreased from a median of 7.0 days/week in the first month in the > or =25-year-old group, 6.3 days/week in the 15-24 year olds, and 6.8 days/week in the 8-14 year olds to 6.5, 3.3, and 3.7 days/week in the 6th month, respectively (P < 0.001 for each age-group). Among subjects with baseline A1C > or =7.0%, CGM use was associated with A1C reduction after 6 months (P = 0.02 adjusted for age-group). Severe hypoglycemia decreased from 27.7 events per 100 person-years in the 6-month control phase of the RCT to 15.0 events per 100 person-years in the 6-month follow-up CGM phase (P = 0.08). Frequent use of CGM in a clinical care setting may improve A1C and reduce episodes of hypoglycemia. However, sustained frequent use of CGM is less likely in children and adolescents than in adults.

To characterize the amount of nocturnal hypoglycemia and evaluate factors associated with nocturnal hypoglycemia assessed with continuous glucose monitoring (CGM) in adults and children with type 1 diabetes who participated in the Juvenile Diabetes Research Foundation CGM randomized clinical trial. The analysis included 36,467 nights with >or=4 h of CGM glucose readings between 12 midnight and 6:00 a.m. from 176 subjects assigned to the CGM group of the trial. The percentage of nights in which hypoglycemia occurred (two consecutive CGM readings or=2 h on 23% of nights with hypoglycemia. In a multivariate model, a higher incidence of nocturnal hypoglycemia was associated with 1) lower baseline A1C levels (P < 0.001) and 2) the occurrence of hypoglycemia on one or more nights during baseline blinded CGM (P < 0.001). The hypoglycemia frequency was not associated with age or with insulin modality (pump versus multiple daily injections). Nocturnal hypoglycemia is frequent and often prolonged in adults and children with type 1 diabetes. Patients with low A1C levels are at an increased risk for its occurrence. One week of blinded CGM can identify patients who are at greater risk for nocturnal hypoglycemia.

The Effect of Continuous Glucose Monitoring in Well-Controlled Type 1 Diabetes Juvenile Diabetes Research Foundation Continuous Glucose Monitoring Study Group * Corresponding author: Roy W. Beck, rbeck{at}jaeb.org . Abstract OBJECTIVE The potential benefits of continuous glucose monitoring (CGM) in the management of adults and children with well-controlled type 1 diabetes have not been examined. RESEARCH DESIGN AND METHODS A total of 129 adults and children with intensively treated type 1 diabetes (age range 8–69 years) and A1C <7.0% were randomly assigned to either continuous or standard glucose monitoring for 26 weeks. The main study outcomes were time with glucose level ≤70 mg/dl, A1C level, and severe hypoglycemic events. RESULTS At 26 weeks, biochemical hypoglycemia (≤70 mg/dl) was less frequent in the CGM group than in the control group (median 54 vs. 91 min/day), but the difference was not statistically significant ( P = 0.16). Median time with a glucose level ≤60 mg/dl was 18 versus 35 min/day, respectively ( P = 0.05). Time out of range (≤70 or >180 mg/dl) was significantly lower in the CGM group than in the control group (377 vs. 491 min/day, P = 0.003). There was a significant treatment group difference favoring the CGM group in mean A1C at 26 weeks adjusted for baseline ( P < 0.001). One or more severe hypoglycemic events occurred in 10 and 11% of the two groups, respectively ( P = 1.0). Four outcome measures combining A1C and hypoglycemia data favored the CGM group in comparison with the control group ( P < 0.001, 0.007, 0.005, and 0.003). CONCLUSIONS Most outcomes, including those combining A1C and hypoglycemia, favored the CGM group. The weight of evidence suggests that CGM is beneficial for individuals with type 1 diabetes who have already achieved excellent control with A1C <7.0%. Footnotes ↵ *The members of the writing committee and the full listing of the members of the Juvenile Diabetes Research Foundation Continuous Glucose Monitoring Study Group can be found in the online appendix available at http://care.diabetesjournals.org/cgi/content/full/dc09-0108/DC1 . Clinical trial reg. no. NCT00406133, clinicaltrials.gov . The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. Received January 20, 2009. Accepted April 27, 2009. © 2009 by the American Diabetes Association.