Safety and Glycemic Outcomes During the MiniMedTM Advanced Hybrid Closed-Loop System Pivotal Trial in Children and Adolescents with Type 1 Diabetes.

Background: During MiniMed™ advanced hybrid closed-loop (AHCL) use by adolescents and adults in the pivotal trial, glycated hemoglobin (A1C) was significantly reduced, time spent in range (TIR) was significantly increased, and there were no episodes of severe hypoglycemia or diabetic ketoacidosis (DKA). The present study investigated the same primary safety and effectiveness endpoints during AHCL use by a younger cohort with type 1 diabetes (T1D). Methods: An intention-to-treat population (N = 160, aged 7-17 years) with T1D was enrolled in a single-arm study at 13 investigational centers. There was a run-in period (∼25 days) using HCL or sensor-augmented pump with/without predictive low-glucose management, followed by a 3-month study period with AHCL activated at two glucose targets (GTs; 100 and 120 mg/dL) for ∼45 days each. The mean ± standard deviation values of A1C, TIR, mean sensor glucose (SG), coefficient of variation (CV) of SG, time at SG ranges, and insulin delivered between run-in and study were analyzed (Wilcoxon signed-rank test or t-test). Results: Compared with baseline, AHCL use was associated with reduced A1C from 7.9 ± 0.9% (N = 160) to 7.4 ± 0.7% (N = 136) (P < 0.001) and overall TIR increased from the run-in 59.4 ± 11.8% to 70.3 ± 6.5% by end of study (P < 0.001), without change in CV, time spent below range (TBR) <70 mg/dL, or TBR <54 mg/dL. Relative to longer active insulin time (AIT) settings (N = 52), an AIT of 2 h (N = 19) with the 100 mg/dL GT increased mean TIR to 73.4%, reduced TBR <70 mg/dL from 3.5% to 2.2%, and reduced time spent above range (TAR) >180 mg/dL from 28.7% to 24.4%. During AHCL use, there was no severe hypoglycemia or DKA. Conclusions: In children and adolescents with T1D, MiniMed AHCL system use was safe, A1C was lower, and TIR was increased. The lowest GT and shortest AIT were associated with the highest TIR and lowest TBR and TAR, all of which met consensus-recommended glycemic targets. ClinicalTrials.gov ID: NCT03959423.

Glycemic Outcomes During Early Use of the MiniMed™ 780G Advanced Hybrid Closed-Loop System with Guardian™ 4 Sensor.

Background: Safety and significant improvement in overall glycated hemoglobin (A1C) and percentage of time spent in (TIR), below (TBR), and above (TAR) glucose range were demonstrated in the pivotal trial of adolescents and adults using the MiniMed™ advanced hybrid closed-loop (AHCL) system with the adjunctive, calibration-required Guardian™ Sensor 3. The present study evaluated early outcomes of continued access study (CAS) participants who transitioned from the pivotal trial investigational system to the approved MiniMed™ 780G system with the non-adjunctive, calibration-free Guardian™ 4 Sensor (MM780G+G4S). Study data were presented alongside those of real-world MM780G+G4S users from Europe, the Middle East, and Africa. Methods: The CAS participants (N = 109, aged 7-17 years and N = 67, aged >17 years) used the MM780G+G4S for 3 months and data of real-world MM780G+G4S system users (N = 10,204 aged ≤15 years and N = 26,099 aged >15 years) were uploaded from September 22, 2021 to December 02, 2022. At least 10 days of real-world continuous glucose monitoring (CGM) data were required for analyses. Glycemic metrics, delivered insulin and system use/interactions underwent descriptive analyses. Results: Time in AHCL and CGM use were >90% for all groups. AHCL exits averaged 0.1/day and there were few blood glucose measurements (BGMs) (0.8/day-1.0/day). Adults in both cohorts met most consensus recommendations for glycemic targets. Pediatric groups met recommendations for %TIR and %TBR, although not those for mean glucose variability and %TAR, possibly due to low use of recommended glucose target (100 mg/dL) and active insulin time (2 h) settings (28.4% in the CAS cohort and 9.4% in the real-world cohort). The CAS pediatric and adult A1C were 7.2% ± 0.7% and 6.8% ± 0.7%, respectively, and there were no serious adverse events. Conclusions: Early clinical use of the MM780G+G4S was safe and involved minimal BGMs and AHCL exits. Consistent with real-world pediatric and adult use, outcomes were associated with achievement of recommended glycemic targets. Clinical Trial Registration number: NCT03959423.

Subcutaneous Infusion of rhPTH1-34 During Pregnancy and Nursing in a Woman With Autosomal Dominant Hypoparathyroidism 1.

We report a successful pregnancy in a young woman with autosomal dominant hypoparathyroidism type 1 (ADH1) due to an activating mutation of the calcium sensing receptor (CASR) (c.2519C>T; p.Ala840Val) who was treated with recombinant human parathyroid hormone (rhPTH)1-34 delivered via continuous subcutaneous infusion using an OmniPod pump. She experienced no tetany or hospitalizations during the pregnancy. Serum calcium levels ranged from 7.2 to 9.8 mg/dL. Due to mild preeclampsia, her infant was delivered at 37 weeks. There were no physical anomalies. The patient continued pump therapy while nursing her daughter, who was ultimately confirmed to have the same CASR mutation. Breastfeeding appeared to protect the infant from significant hypocalcemia without the need for calcium or calcitriol supplementation until weaning at a year of age. A role for parathyroid hormone-related protein (PTHrP) is suggested.

Glycemic outcomes of children 2-6 years of age with type 1 diabetes during the pediatric MiniMed™ 670G system trial.

BACKGROUND: Highly variable insulin sensitivity, susceptibility to hypoglycemia and inability to effectively communicate hypoglycemic symptoms pose significant challenges for young children with type 1 diabetes (T1D). Herein, outcomes during clinical MiniMed™ 670G system use were evaluated in children aged 2-6 years with T1D. METHODS: Participants (N = 46, aged 4.6 ± 1.4 years) at seven investigational centers used the MiniMed™ 670G system in Manual Mode during a two-week run-in period followed by Auto Mode during a three-month study phase. Safety events, mean A1C, sensor glucose (SG), and percentage of time spent in (TIR, 70-180 mg/dl), below (TBR, <70 mg/dl) and above (TAR, >180 mg/dl) range were assessed for the run-in and study phase and compared using a paired t-test or Wilcoxon signed-rank test. RESULTS: From run-in to end of study (median 87.1% time in auto mode), mean A1C and SG changed from 8.0 ± 0.9% to 7.5 ± 0.6% (p < 0.001) and from 173 ± 24 to 161 ± 16 mg/dl (p < 0.001), respectively. Overall TIR increased from 55.7 ± 13.4% to 63.8 ± 9.4% (p < 0.001), while TBR and TAR decreased from 3.3 ± 2.5% to 3.2 ± 1.6% (p = 0.996) and 41.0 ± 14.7% to 33.0 ± 9.9% (p < 0.001), respectively. Overnight TBR remained unchanged and TAR was further improved 12:00 am-6:00 am. Throughout the study phase, there were no episodes of severe hypoglycemia or diabetic ketoacidosis (DKA) and no serious adverse device-related events. CONCLUSIONS: At-home MiniMed™ 670G Auto Mode use by young children safely improved glycemic outcomes compared to two-week open-loop Manual Mode use. The improvements are similar to those observed in older children, adolescents and adults with T1D using the same system for the same duration of time.

Safety and Glycemic Outcomes During the MiniMed™ Advanced Hybrid Closed-Loop System Pivotal Trial in Adolescents and Adults with Type 1 Diabetes.

Introduction: This trial assessed safety and effectiveness of an advanced hybrid closed-loop (AHCL) system with automated basal (Auto Basal) and automated bolus correction (Auto Correction) in adolescents and adults with type 1 diabetes (T1D). Materials and Methods: This multicenter single-arm study involved an intent-to-treat population of 157 individuals (39 adolescents aged 14-21 years and 118 adults aged ≥22-75 years) with T1D. Study participants used the MiniMed™ AHCL system during a baseline run-in period in which sensor-augmented pump +/- predictive low glucose management or Auto Basal was enabled for ∼14 days. Thereafter, Auto Basal and Auto Correction were enabled for a study phase (∼90 days), with glucose target set to 100 or 120 mg/dL for ∼45 days, followed by the other target for ∼45 days. Study endpoints included safety events and change in mean A1C, time in range (TIR, 70-180 mg/dL) and time below range (TBR, <70 mg/dL). Run-in and study phase values were compared using Wilcoxon signed-rank test or paired t-test. Results: Overall group time spent in closed loop averaged 94.9% ± 5.4% and involved only 1.2 ± 0.8 exits per week. Compared with run-in, AHCL reduced A1C from 7.5% ± 0.8% to 7.0% ± 0.5% (<0.001, Wilcoxon signed-rank test, n = 155), TIR increased from 68.8% ± 10.5% to 74.5% ± 6.9% (<0.001, Wilcoxon signed-rank test), and TBR reduced from 3.3% ± 2.9% to 2.3% ± 1.7% (<0.001, Wilcoxon signed-rank test). Similar benefits to glycemia were observed for each age group and were more pronounced for the nighttime (12 AM-6 AM). The 100 mg/dL target increased TIR to 75.4% (n = 155), which was further optimized at a lower active insulin time (AIT) setting (i.e., 2 h), without increasing TBR. There were no severe hypoglycemic or diabetic ketoacidosis events during the study phase. Conclusions: These findings show that the MiniMed AHCL system is safe and allows for achievement of recommended glycemic targets in adolescents and adults with T1D. Adjustments in target and AIT settings may further optimize glycemia and improve user experience. Clinical Trial Registration number: NCT03959423.

Recombinant human parathyroid hormone (1-84) is effective in CASR-associated hypoparathyroidism.

INTRODUCTION: Gain-of-function mutations in the CASR gene cause Autosomal Dominant Hypocalcemia Type 1 (ADH1), the most common genetic cause of isolated hypoparathyroidism. Subjects have increased calcium sensitivity in the renal tubule, leading to increased urinary calcium excretion, nephrocalcinosis and nephrolithiasis when compared with other causes of hypoparathyroidism. The traditional approach to treatment includes activated vitamin D but this further increases urinary calcium excretion. METHODS: In this case series, we describe the use of recombinant human parathyroid hormone (rhPTH)1-84 to treat subjects with ADH1, with improved control of serum and urinary calcium levels. RESULTS: We describe two children and one adult with ADH1 due to heterozygous CASR mutations who were treated with rhPTH(1-84). Case 1 was a 9.4-year-old female whose 24-h urinary calcium decreased from 7.5 to 3.9 mg/kg at 1 year. Calcitriol and calcium supplementation were discontinued after titration of rhPTH(1-84). Case 2 was a 9.5-year-old male whose 24-h urinary calcium decreased from 11.7 to 1.7 mg/kg at 1 year, and calcitriol was also discontinued. Case 3 was a 24-year-old female whose treatment was switched from multi-dose teriparatide to daily rhPTH(1-84). All three subjects achieved or maintained target serum levels of calcium and normal or improved urinary calcium levels with daily rhPTH(1-84) monotherapy. CONCLUSIONS: We have described three subjects with ADH1 who were treated effectively with rhPTH(1-84). In all cases, hypercalciuria improved by comparison to treatment with conventional therapy consisting of calcium supplementation and calcitriol.

Safety Evaluation of the MiniMed 670G System in Children 7-13 Years of Age with Type 1 Diabetes.

OBJECTIVE: To evaluate the safety of in-home use of the MiniMed™ 670G system with SmartGuard™ technology in children with type 1 diabetes (T1D). METHODS: Participants (N = 105, ages 7-13 years, mean age 10.8 ± 1.8 years) were enrolled at nine centers (eight in the United States and one in Israel) and completed a 2-week baseline run-in phase in Manual Mode followed by a 3-month study phase with Auto Mode enabled. Sensor glucose (SG), glycated hemoglobin (HbA1c), percentage of SG values across glucose ranges, and SG variability, during the run-in and study phases were compared. Participants underwent frequent sample testing with i-STAT® venous reference measurement during a hotel period (6 days/5 nights) to evaluate the system's continuous glucose monitoring performance. RESULTS: Auto Mode was used a median of 81% of the time. From baseline to end of study, overall SG dropped by 6.9 ± 17.2 mg/dL (P < 0.001), HbA1c decreased from 7.9% ± 0.8% to 7.5% ± 0.6% (P < 0.001), percentage of time in target glucose range (70-180 mg/dL) increased from 56.2% ± 11.4% to 65.0% ± 7.7% (P < 0.001), and the SG coefficient of variation decreased from 39.6% ± 5.4% to 38.5% ± 3.8% (P = 0.009). The percentage of SG values within target glucose range was 68.2% ± 9.1% and that of i-STAT reference values was 65.6% ± 17.7%. The percentage of values within 20%/20 of the i-STAT reference was 85.2%. There were no episodes of severe hypoglycemia or diabetic ketoacidosis during the study phase. CONCLUSION: In-home use of MiniMed 670G system Auto Mode for 3 months by children with T1D, similar to MiniMed 670G system use by adolescents and adults with T1D, was safe and associated with reduced HbA1c levels and increased time in target glucose range, compared with baseline.

In-Clinic Evaluation of the MiniMed 670G System "Suspend Before Low" Feature in Children with Type 1 Diabetes.

BACKGROUND: The Medtronic predictive low-glucose management (PLGM) algorithm automatically stops insulin delivery when sensor glucose (SG) is predicted to reach or fall below a preset low-glucose value within the next 30 min, and resumes delivery after hypoglycemia recovery. The present study evaluated the PLGM algorithm performance of the MiniMed™ 670G system SmartGuard™ "suspend before low" feature in children aged 7-13 years with type 1 diabetes (T1D). METHOD: Participants (N = 105, mean ± standard deviation of 10.8 ± 1.8 years) underwent an overnight in-clinic evaluation of the "suspend before low" feature with a preset low limit of 65 mg/dL. After exercise, frequent sample testing (FST) was conducted every 5 min if values were <70 mg/dL; every 15 min if 70-80 mg/dL; and every 30 min if >80 mg/dL. First-day performance of the Guardian™ Sensor 3 glucose sensor and continuous glucose monitoring system was also evaluated. RESULTS: Activation of the "suspend before low" feature occurred in 79 of the 105 participants, 79.7% (63/79) did not result in SG falling below 65 mg/dL. Mean glucose at activation was 102 ± 19 mg/dL and the initial insulin suspension duration was 87.5 ± 32.7 min. Four hours after insulin resumption, mean reference glucose was 130 ± 42 mg/dL. Mean absolute relative difference between the FST reference glucose and SG values on the first day of sensor wear was 11.4%. For the 26 participants in whom the "suspend before low" feature did not activate, none involved a reference glucose value ≤65 mg/dL, suggesting that the PLGM algorithm performed as intended. CONCLUSION: In children aged 7-13 years with T1D, the "suspend before low" feature of the MiniMed 670G system demonstrated a hypoglycemia prevention rate of nearly 80% after exercise and did not involve rebound hyperglycemia. There were no events of severe hypoglycemia during the evaluation.

A novel mutation in GLUD1 causing hyperinsulinism-hyperammonemia in a patient with high density of homozygosity on microarray: a case report.

BACKGROUND: Hyperinsulinism-hyperammonemia syndrome is the second most common cause of congenital hyperinsulinism and is easily treated with diazoxide; however, the symptoms in our patient were very difficult to control with typical medical therapy. To the best of our knowledge, neither our patient's mutation, nor a case of hyperinsulinism-hyperammonemia presenting with dysmorphic features and intrauterine growth restriction has previously been reported. CASE PRESENTATION: We describe a 2-year-old Hispanic girl with an unusual presentation of dysmorphic features and intrauterine growth restriction who was later found to have hyperinsulinism-hyperammonemia syndrome. Chromosomal microarray analysis revealed no copy number variants but demonstrated a high density of noncontiguous regions of homozygosity consistent with limited outbreeding. Sequencing of her GLUD1 gene revealed a previously undescribed mutation of cytosine to thymine at position 1519 resulting in an amino acid change of histidine to tyrosine at position 507. Although no functional studies were performed, function prediction tools in combination with our patient's phenotype support the hypothesis that the mutation is deleterious. Despite treatment with a maximum dose of diazoxide (15 mg/kg/day), phenobarbital (8.5 mg/kg/day divided twice daily) and a protein-restricted diet, she has global developmental delay, and continues to have seizures and recurrent episodes of hypoglycemia. CONCLUSIONS: It remains unclear if her clinical presentation can be solely explained by hyperinsulinism-hyperammonemia syndrome or is the result of an undiagnosed recessive disorder related to her homozygosity. It is our hope that clinicians may learn from our patient when formulating treatment plans for refractory cases of hyperinsulinism-hyperammonemia and avoid the morbidities associated with delayed diagnosis and treatment.

Poor head growth as a presenting sign of a cortisol-secreting adrenal adenoma in a 2-year-old boy.

Typical signs of glucocorticoid excess in children are weight gain and poor linear growth. We describe a 2-year-old boy with a cortisol-secreting adenoma who presented with a dramatic decline in head growth. This case underscores concern of adverse effects of excess glucocorticoid on brain growth in very young children.

Hyperparathyroidism two years after radioactive iodine therapy in an adolescent male.

Primary hyperparathyroidism is a very rare complication following radioactive iodine therapy. There is typically a latency period of more than a decade following radiation exposure and, therefore, it is observed almost exclusively in adults. Consequently, pediatricians are not aware of the association. We present a case of primary hyperparathyroidism due to a solitary parathyroid adenoma occurring in an adolescent male two years following radioactive iodine treatment for papillary thyroid carcinoma. Periodic screening of serum calcium following ablative doses of radioactive iodine for thyroid cancer may be justified even in adolescents.

Novel method to characterize CYP21A2 in Florida patients with congenital adrenal hyperplasia and commercially available cell lines.

Congenital adrenal hyperplasia (CAH) is an autosomal recessive disorder and affects approximately 1 in 15,000 births in the United States. CAH is one of the disorders included on the Newborn Screening (NBS) Recommended Uniform Screening Panel. The commonly used immunological NBS test is associated with a high false positive rate and there is interest in developing second-tier assays to increase screening specificity. Approximately 90% of the classic forms of CAH, salt-wasting and simple virilizing, are due to mutations in the CYP21A2 gene. These include single nucleotide changes, insertions, deletions, as well as chimeric genes involving CYP21A2 and its highly homologous pseudogene CYP21A1P. A novel loci-specific PCR approach was developed to individually amplify the CYP21A2 gene, the nearby CYP21A1P pseudogene, as well as any 30 kb deletion and gene conversion mutations, if present, as single separate amplicons. Using commercially available CAH positive specimens and 14 families with an affected CAH proband, the single long-range amplicon approach demonstrated higher specificity as compared to previously published methods.

Progressive central puberty in a toddler with partial androgen insensitivity.

A male infant was diagnosed with partial androgen insensitivity caused by a novel mutation in the androgen receptor. At 3.5 months of age, he received 100 mg of testosterone intramuscularly over the course of 3 months to increase phallic size. He developed pubic hair after 5 months and signs of progressive central precocious puberty when re-examined at 17.5 months, which subsequently was suppressed with depot leuprolide.

Characteristics of children with the best and poorest first- and second-year growth during rhGH therapy: data from 25 years of the Genentech national cooperative growth study (NCGS).

BACKGROUND: Models assessing characteristics contributing to response to recombinant human growth hormone (rhGH) response rarely address growth extremes in both years 1 and 2 or examine how children track from year to year. Using National Cooperative Growth Study (NCGS) data, we determined characteristics contributing to responsiveness to rhGH and the pattern of change from years 1 to 2. PATIENTS AND METHODS: Height velocity standard deviation score (HV SDS) for 2 years for prepubertal children with idiopathic GH deficiency (IGHD) (n = 1899) and idiopathic short stature (ISS) (n = 1186) treated with similar doses for two years were computed. Group 1 = HV SDS < -1; 2 = HV SDS -1 to +1; 3 = HV SDS > +1. RESULTS: For IGHD, mean age was 7.5 years and similar in all groups. Year 1 HV SDS was associated with greater body mass index (BMI) SDS, lower pre-treatment HV, baseline height SDS, greater target height SDS minus height SDS, and lower maximum stimulated GH (P <0.0001). Year 2, 172/271 (73%) in group 1 moved to either group 2 (n = 156) or 3 (n = 16). Year 2 HV SDS was associated with greater year 1 HV SDS (r = 0.045, P <0.0001), greater BMI SDS, taller parents and lower peak GH.For ISS, year 1 HV SDS was associated with greater BMI SDS and lower pre-treatment HV (P ≤0.0001). 109/169 (64%) in group 1 moved to group 2 (n = 90) or group 3 (n = 19). Greater year 2 HV SDS was related to year 1 HV SDS (r = 0.27, P <0.0001). CONCLUSION: For IGHD, multiple characteristics contributed to best first-year response but for ISS, best first-year HV SDS was associated only with BMI SDS and inversely with pre-treatment HV. For both GHD and ISS, year 1 HV SDS was not a strong enough predictor of year 2 HV SDS to use first-year HV alone to determine GH continuation.

Is there "seasonal" variation in height velocity in children treated with growth hormone? Data from the National Cooperative Growth Study.

BACKGROUND: Growth rate In children is reported to have seasonal variability. There are fewer published data regarding seasonal variability while on growth hormone (GH) therapy, and none analyzing growth rate with respect to number of daylight hours. METHODS: We analyzed 11,587 3-month intervals in 2277 prepubertal children (boys ages 3-14 years, girls ages 3-12 years) with idiopathic GH deficiency from the National Cooperative Growth Study (NCGS) database. All were naive to recombinant human GH (rhGH) therapy. Data were submitted from 31 US study centers. Seasonal variation in height velocity (HV) was assumed to be associated with the average number of daylight hours during the interval of time over which HV was computed. Number of daylight hours was determined from the date of the measurement and the latitude of the study center. Other independent variables evaluated included: height standard deviation score (SDS) at the beginning of the interval, chronologic age at the beginning of the interval, time from the start of rhGH treatment to the middle of the interval, month of the year, body mass index SDS at the beginning of the interval, rhGH dose/kg, mother's height SDS, father's height SDS, and log base 10 of the maximum stimulated GH concentration. RESULTS: All variables examined, except month of the year, correlated significantly with interval HV. There was significant "seasonal" variability at all latitudes, with summer annualized HV being greater than winter HV. This difference was greatest in the first year of therapy (0.146 cm/yr/daylight hour; P < 0.0001) but persisted in subsequent years (0.121 cm/yr/daylight hr; P < 0.0001). The difference increased with distance from the equator. Growth rate over the year was not different among the latitudes reflected in this North American study. CONCLUSIONS: There is "seasonal" variation in growth of children on rhGH therapy that correlates with number of daylight hours. The effect is modest and is greatest in the first year of therapy. Annual growth rate appears to be equal in children among latitudes covered by the US consistent with exposure to an equal number of daylight hours over the year. The physiologic mechanism behind this seasonal variation is not yet understood.

Natural history of idiopathic diabetes insipidus.

OBJECTIVE: To determine what percentage of diabetes insipidus (DI) in childhood is idiopathic and to assess the natural history of idiopathic DI. STUDY DESIGN: We conducted a retrospective chart review of 105 patients with DI who were born or had DI diagnosed between 1980-1989 at 3 medical centers. A second cohort of 30 patients from 6 medical centers in whom idiopathic DI was diagnosed after 1990 was evaluated retrospectively for subsequent etiologic diagnoses and additional hypothalamic/pituitary deficiencies and prospectively for quality of life. RESULTS: In the first cohort, 11% of patients had idiopathic DI. In the second cohort, additional hypothalamic/pituitary hormone deficiencies developed in 33%, and 37% received an etiologic diagnosis for DI. Health-related quality of life for all the patients with idiopathic DI was comparable with the healthy reference population. CONCLUSIONS: Only a small percentage of patients with DI will remain idiopathic after first examination. Other hormone deficiencies will develop later in one-third of those patients, and slightly more than one-third of those patients will have an etiology for the DI diagnosed. Long-term surveillance is important because tumors have been diagnosed as long as 21 years after the onset of DI. Quality of life for these patients is as good as the reference population.