Alessandra Maestro

Driven by technological advances and regulatory developments, the clinical trials industry is undergoing a period of transformation. Decentralized clinical trials (DCTs) promise to streamline processes, increase participant engagement and improve data quality. The pediatric clinical trial landscape is challenging, as participation in a clinical trial affects the whole family. DCTs allow for increased patient engagement, thereby improving trial quality and consequently drug safety. The Italian Medicines Agency (AIFA), in its quest for regulatory simplification and alignment with the European framework, has established comprehensive guidelines to facilitate these decentralized trials. The present work aims to delve into the regulations to understand the feasibility of conducting decentralized pediatric trials in Italy.

Background: Pediatric patients undergoing allogeneic hematopoietic stem cell transplantation (allo-HSCT) face several risk factors influencing transplantation success, including nutritional status as measured by body mass index (BMI). Methods: This study analyzed BMI data collected from patients transplanted between 2003 and 2023, and aimed to evaluate whether deviations from normal BMI are associated with poorer clinical outcomes. BMI levels assessed before and after first-line treatment and pre-transplantation were analyzed retrospectively to determine a correlation with survival and post-transplant complications. Results: Underweight patients had significantly lower 12- and 36-month overall survival rates compared to normal-weight and overweight patients (p = 1.22 × 10⁻⁸ and p = 8.88 × 10⁻⁸, respectively). Event-free survival was also lower for underweight patients at all time points. A higher pre-transplant BMI increases the risk of acute graft-versus-host disease (GVHD, p = 0.00068). Otherwise, pre-transplant BMI was not significantly correlated with early TRCs and cGVHD. As secondary objectives, this study identified differences in BMI across primary disease groups, with solid tumor patients having the highest BMI and myelodysplastic syndrome patients having the lowest. BMI cut-offs were identified to predict or protect against serious outcomes, including delayed engraftment, TRCs, and acute and chronic GVHD. Conclusions: This study highlights the importance of nutritional assessment and management in pediatric patients undergoing allo-HSCT to optimize post-transplant outcomes, as deviations from a normal BMI can significantly impact post-transplant health. These findings underscore the importance of integrating BMI assessment throughout the entire pre-HSCT therapeutic course to identify patients at higher risk for complications and to define more effective nutritional management strategies.

Glycopyrrolate is a competitive muscarinic receptor antagonist used in the treatment of sialorrhea, especially in pediatrics. Degradation research was conducted to better understand the stability of the active pharmaceutical ingredient (API). Using an HPLC-UV method, we evaluated the chemical stability of the oral solution of the galenic compound glycopyrrolate 0.5 mg/mL under different storage conditions. Method validation was performed according to the International Council for Harmonization (ICH) Q2(R2) guidelines. The results of the stability study of the galenic compound in different storage conditions, with the exception of those stored in glass containers at 45 °C for more than 3 months, were stable (100 ± 10% of the nominal concentration). The aim of this work was to study the stability of the galenic compound glycopyrrolate in two different types of containers and at three different storage temperatures. Glycopyrrolate showed degradation beyond the limits only in glass at 45 °C and after 2 months of storage. The results indicate that oral liquid dosage forms of glycopyrrolate are stable for at least 210 days when stored at room temperature or at 4 °C, in glass or PET, for at least 7 months, maintaining product quality according to the standards established by the European Pharmacopoeia, ensuring long-term coverage for pediatric patient therapies.

Gender-based medicine is attracting increasing interest every day, but studies on pediatric populations are still limited. In this setting, sex differences among patients undergoing total parenteral nutrition (TPN) have not been previously reported. This study investigated the presence of sex differences in parenteral nutrition composition and outcomes among a cohort of pediatric patients admitted at the Oncohematology and Bone Marrow Transplant Unit of the Institute for Maternal and Child Health “Burlo Garofolo” of Trieste, Italy. For all 145 recruited patients (87 males, 58 females), the following data were collected: age, sex, volume and duration of TPN, macro- and micronutrient composition of TPN bags, electrolytic or blood gases imbalance, glycolipid alterations, liver damage during TPN, and the incidence of sepsis and thrombosis. The analysis showed that females required higher daily phosphate intake (p = 0.054) and essential amino acid supplementation (p = 0.07), while males had a higher incidence of hypertriglyceridemia (p < 0.05) and cholestasis. A higher incidence of sepsis was found in the non-transplanted male population (p < 0.05). No significant differences were appreciable in other analyzed variables. This study aims to create a basis for future gender-based nutritional recommendations in the pediatric field.

Evinacumab, a human monoclonal antibody against angiopoietin-like protein 3 (ANGPTL3), has recently been approved by the U.S. Food and Drug Administration as an add-on therapy for homozygous familial hypercholesterolemia (HoFH) in patients of 12 years and older. Its role as a triglyceride-lowering drug is also emerging in the literature. However, it has not been approved for this indication yet, neither in the adult nor in the pediatric population. We describe the case of a 10-year-old boy who underwent an allogeneic hematopoietic stem cell transplant for acute lymphoblastic leukemia complicated by chronic graft-versus-host disease (GVHD) and presented life-threatening refractory hypertriglyceridemia due to the concomitant use of ruxolitinib and sirolimus. After the failure of the insulin treatment and due to the technical impossibility of performing lipid apheresis, the child underwent evinacumab treatment, obtaining a dramatic rapid reduction in triglyceride and cholesterol levels. This is the first report of a pediatric patient younger than 12 years in Europe receiving evinacumab to treat severe hypertriglyceridemia. The therapy with angiopoietin-like proteins inhibitors has been effective, safe, and well-tolerated in our patient, suggesting that evinacumab may be used in the pediatric population when other therapeutic strategies are ineffective or contraindicated.

The high serum concentrations of TNF-α characterize acute graft-versus-host disease (aGVHD), for which infliximab treatment may be beneficial. In 28 pediatric patients, four doses of 10 mg/kg infliximab every seven days were administered after steroid failure (Standard Group, n = 14) or as a first-line therapy (Early Group, n = 14). Population pharmacokinetic analyses and evaluation of serum cytokines were performed. After two months of treatment, complete response in gastrointestinal and liver aGVHD was achieved in 43% and 100% of patients in the Standard and Early groups, respectively. During follow-up, four patients in the Standard Group (but none in the Early Group) experienced an aGVHD recurrence. Viral infections occurred more frequently in the Standard Group after the fifth dose. Infliximab clearance did not differ between groups or according to treatment outcome for each organ involved in aGVHD, whereas serum levels of cytokines significantly differed. Therefore, present findings show that use of first-line, TDM-driven infliximab to treat aGVHD in children may result in better clinical outcomes and tolerability, with a different pattern of cytokines generated according to the moment of beginning of treatment.

Evinacumab, a human monoclonal antibody against angiopoietin-like protein 3 (ANGPTL3), has recently been approved by U.S. Food and Drug Administration as an add-on therapy for homozygous familial hypercholesterolemia (HoFH) in patients of 12 years and older. Its role as a triglyceride-lowering drug is also emerging in the literature. However, it has not been approved for this indication yet, neither in the adult nor in the pediatric population. We describe the case of a 10-year-old boy who underwent an allogeneic hematopoietic stem cell transplant for acute lymphoblastic leukemia complicated by chronic graft–versus–host disease (GVHD) and presented life-threatening refractory hypertriglyceridemia due to the concomitant use of ruxolitinib and sirolimus. After the failure of the insulin treatment and due to the technical impossibility of performing lipid apheresis, we underwent the child to evinacumab treatment, obtaining a dramatic rapid reduction in triglyceride and cholesterol levels. This is the first report of a pediatric patient younger than 12 years in Europa receiving evinacumab to treat severe hypertriglyceridemia. The therapy with angiopoietin-like proteins inhibitors has been effective, safe, and well-tolerated in our patient, suggesting that evinacumab may be used in the pediatric population when other therapeutic strategies are ineffective or contraindicated.

Familial hypomagnesemia with hypercalciuria and nephrocalcinosis (FHHNC) is a rare autosomal recessive disorder affecting <1/1,000,000 people. It is caused by mutations in the CLDN16 (FHHNC Type 1) or CLDN19 (FHHNC Type 2) genes, which are located on Chromosomes 3q27 and 1p34.2, respectively. There are no drug therapies for this condition. Although magnesium salts represent an important class of compounds and exhibit various therapeutic actions as a supplement for magnesium deficiency in FHHNC, various formulations on the market have different bioavailability. We report the case of a patient with FHNNC first treated, in our Pediatric Institute, with high doses of magnesium pidolate and magnesium and potassium citrate. The patient began to neglect this therapy after experiencing frequent daily episodes of diarrhoea. Our pharmacy received a request for an alternative magnesium supplement that would better comply by ensuring a good magnesium intake which will result in adequate blood magnesium levels. In response, we developed a galenic compound in the form of effervescent magnesium. Here, we report on the promise of this formulation not only for better compliance than pidolate, but also for better bioavailability.

The use of anti-thymocyte globulin (ATG) as part of conditioning to prevent graft-versus-host disease (GVHD) may severely impair immune reconstitution (IR). We analyzed relationships between ATG exposure, the recipient lymphocyte count, IR, and transplant outcome. We retrospectively reviewed patients aged ≤ 18 years who underwent allogeneic HSCT between April 2005 and April 2020. The outcomes of interest included the incidence of GVHD, overall survival (OS), and IR. IR was analyzed through thymic magnetic resonance imaging (MRI) and by quantifying T CD4+ and recent thymic emigrants (RTEs). The ATG-exposed group was split into a low ATG/lymphocyte ratio subgroup (ratio < 0.01) and a high ATG/lymphocyte ratio subgroup (ratio > 0.01). The low ratio subgroup had a higher incidence of GVHD (29 [59%] vs. 7 [16.6%]) but a better IR in both laboratory and MRI imaging assessments (p < 0.0001). The median thymic volume in the low ratio subgroup was significantly higher (14.7 cm³ vs. 4.5 cm³, p < 0.001). This was associated with a better OS and lower transplant-related mortality (TRM) (80.4% vs. 58.0%, p = 0.031) and (13.1% vs. 33.0%, p = 0.035). An individualized approach to ATG dosing allows for the obtainment of rapid thymic reconstitution and the best transplant-related outcomes.