Hypocalcemia

Primary endpoints were pharmacokinetic parameters, including the area under the serum-concentration time curve (AUC_{0–113 days}) and maximum concentration (C_max). The pharmacokinetic analyses included all subjects for whom the pharmacokinetic parameters could be derived. One subject in the normal group was lost to follow-up after day 14 and was excluded from all other pharmacokinetic analyses. Means for each renal function group were calculated. A nonparametric test for trend analysis was used to assess the effect of decreasing renal function on denosumab disposition. Regression analysis was used to model the relationship between the values of the pharmacokinetic parameters and GFR.
Secondary endpoints included subject incidences of adverse events, clinically significant changes in vital signs, physical examinations, clinical laboratory tests, ECGs, and incidence of anti-denosumab antibodies. Subject incidences of albumin-adjusted serum calcium concentrations <8.0 mg/dL (<2.0 mmol/L), albumin-adjusted serum calcium concentration <7.5 mg/dL (<1.9 mmol/L), serious adverse events of hypocalcemia, and symptomatic adverse events of hypocalcemia were evaluated by renal function group. A post hoc multivariate analysis was conducted to evaluate the association between mean decrease from baseline to nadir serum calcium concentration and baseline characteristics (age, race, sex, CKD stage, serum calcium, serum phosphorus, iPTH, 25-OHD, and 1,25-(OH)₂D). Proportions were calculated for subjects with at least a 50% reduction in GFR using the Modification of Diet in Renal Disease (MDRD) equation.23 (link)
Change in sCTX1 concentrations was an exploratory pharmacodynamic endpoint; sCTX1 values below the limit of quantification were set to zero. The Spearman correlation coefficient was calculated for maximum absolute decrease in sCTX1 and (1) baseline iPTH and (2) baseline alkaline phosphatase.
The planned sample size of 46 subjects (12 with normal renal function, 10 each with mild and moderate CKD, 7 with severe CKD, and 7 with kidney failure) was based on practical considerations. After the study protocol was amended to include calcium and vitamin D supplementation, enrollment was increased to include 13 subjects each in the mild CKD and moderate CKD groups, and 8 to 9 subjects each in the severe CKD and kidney failure groups.

• Maternal data that are prospectively collected are: pregnancy duration, preeclampsia (de novo BP ≥140/90 mmHg > 20 weeks with proteinuria or signs of end-organ dysfunction), eclampsia, HELLP syndrome (according to the Tenessee criteria) [36 ], gestational hypertension (de novo BP ≥140/90 mmHg > 20 weeks), preexisting hypertension, pregnancy-induced cholestasis, ultrasound data on the presence of hydramnios (amniotic fluid index >25 cm), abdominal circumference ≥ P95 and estimated fetal weight ≥ P90 or ≤ P10.
• Delivery data that are prospectively collected are: type of labor (spontaneous, induced or caesarean before labor) and the indications if appropriate, type of delivery (spontaneous vaginal, forceps or vacuum, caesarean section during labor or planned caesarean section) and the indications if appropriate.
• Neonatal data that are prospectively collected are: macrosomia (>4 Kg), LGA (birth weight >90 percentile according to standardized Flemish birth charts adjusted for sex of the baby and parity), small for gestational age (birth weight <10 percentile according to standardized Flemish birth charts adjusted for sex of the baby and parity), preterm delivery (<37 completed weeks), 1 and 5 min Apgar score, shoulder dystocia, birth trauma, neonatal respiratory distress syndrome, congenital anomalies, neonatal hypoglycaemia, neonatal jaundice, hypocalcaemia, hypomagnesemia, polycythaemia and duration and indication for admission on the neonatal intensive care unit. Neonatal blood analyses are only done if there is a clinical warning sign in accordance with local practice.
Researchers are asked to evaluate whether the main reason of the maternal and neonatal complications and management is related to diabetes or GDM.

The predictor variable was surgical technique, i.e., TT with versus without pCNLD, which were recorded as a binary parameter. In the TT-alone group, the patients were totally thyroidectomized due to the incidental finding of the cancer after the final pathological report with the patient’s willingness (consent). The main outcome variables included: (1) complications, that is, recurrent laryngeal nerve (RLN) palsy, temporary and permanent hypoparathyroidism, postoperative bleeding, injury to adjacent organ (esophagus, trachea, etc.); (2) recurrence parameters. The vocal cord status was assessed by routine pre- and postoperative indirect laryngoscopy and ultrasound. Temporary vocal cord palsy was defined as decreased or absent vocal cord mobility that resolved within 6 months after surgery. Permanent vocal cord palsy was defined as vocal cord dysfunction persisting more than 6 months after the initial surgery. To determine hypoparathyroidism, serum calcium levels were investigated preoperatively and on each postoperative day. Parathyroid hormone (PTH) levels were tested daily (normal level: 12–88 pg/mL). Symptomatic hypocalcemia was diagnosed if the calcium level was <2.17 mmol/L and patients complained of any symptoms (such as perioral and digital paresthesia, tetany, and palpitation), irrespective of the duration of hospital stay. Routine calcium supplementation was given to all patients. Permanent hypocalcemia or hypoparathyroidism was defined as an ongoing need for calcium or vitamin D supplementation >12 months.
The other study parameters were (1) demographic (age and gender) and (2) tumor-related (tumor staging, TNM status, and histopathological results). Age was recorded as a continuous parameter, gender was categorized into binary, and the tumor status was assessed as nominal scales.

The study drug was TZP. All other drugs were used as comparators for signal detection of TZP-related EDs. The 10 most important and popular EDs were selected to assess TZP-associated EDs: hypokalemia, hyperkalemia, hyponatremia, hypernatremia, hypocalcemia, hypercalcemia, hypomagnesemia, hypermagnesemia, hypophosphatemia, and hyperphosphatemia. The MedDRA preferred terms used for the extraction of EDs were as follows: “hypokalaemia”, “blood potassium decreased”, “hyperkalaemia”, “blood potassium increased”, “hyponatraemia”, “blood sodium decreased”, “hypernatraemia”, “blood sodium increased”, “hypocalcaemia”, “blood calcium decreased”, “hypercalcaemia”, “blood calcium increased”, “hypomagnesaemia”, “blood magnesium decreased”, “hypermagnesaemia”, “blood magnesium increased”, “hypophosphataemia”, “blood phosphorus decreased”, “hyperphosphataemia”, and “blood phosphorus increased”.
The PCNs used as comparators are listed in Table 6. We selected PCNs that had been used in the United States during the study period and flucloxacillin, which was not available in the US but is commonly used in European Union countries.