All 23 pediatric patients screened were enrolled in the study. Two of these discontinued due to unrelated adverse events (after week 2 and after week 36). The remaining 21 pediatric patients completed the study. Of 28 adults enrolled, 22 completed the study.
The proportion of females among children was three times lower than that of males (Table I), due to the high proportion of patients with XLA (all males).
Study Drug Administration
All patients in the ITT population received the intended 12 infusions during the wash-in/wash-out period. Most patients received the planned 40 infusions during the study: 16 children (94%), five adolescents (80%), and 17 (71%) adults. Five adults (21%) received 41 infusions.
The mean (SD) of individual median Hizentra® doses per week for the entire study period was 129.9 (46.2) mg/kg bw in children (range, 76–262 mg/kg bw) and 113.7 (28.0) mg/kg bw in adolescents (range, 72–150 mg/kg bw), both very similar to the dose of 114.3 (27.6) mg/kg bw administered in adults (range, 59–189 mg/kg bw).
Dose increases of >10% of the planned dose were made in four children and one adolescent during the wash-in/wash-out period. One child and one adolescent had dose decreases of >10%. Dose adjustments in adults were not necessary.
The mean of the individual median infusion rates was lower in children (19.0 mL/h) compared to adolescents and adults (31.2 and 28.5 mL/h, respectively). The median duration of infusion per week was 0.78 h (range, 0.3–2.5 h) in children and 1.0 h (range, 0.5–2.5 h) in adolescents, which was lower than that in adults (1.42 h; range, 0.7–3.3 h) because of the higher total dose administered in adults.
Primary Efficacy Endpoint
The study objective was met: Hizentra® treatment resulted in serum IgG trough levels comparable to or higher than those achieved with previous therapy. The mean of the individual pre-study median IgG trough level in children was 6.94 g/L, and in adolescents, 7.99 g/L compared with 7.81 g/L in adults (Table III). The mean of the individual median IgG trough levels measured before Infusions 12 to 17 were 7.86 g/L in children, and 7.91 g/L in adolescents compared with 8.31 g/L in adults, suggesting that IgG levels were maintained in all age groups.
Children achieved the largest increase in mean of the individual median IgG trough levels from baseline to study end (13.3%), while the change in adolescents and adults was small (Fig. 1). Most likely, this observation was due to the fact that two thirds of the children (n = 11) had been treated with IVIG prior to the study and had a pre-study IgG trough level of 6.47 g/L (mean of individual medians). The IgG trough level measured before Infusions 12 to 17 in these children was 7.92 g/L (mean of individual medians), which corresponded to an increase of 22.4%. In comparison, the pre-study IgG trough level in children previously treated with SCIG (n = 6, mean of individual medians 7.80 g/L) was similar to the level achieved with Hizentra®. The four adolescents who had previously been on SCIG had a pre-study IgG trough level of 8.65 g/L (mean of individual medians). Adults previously treated with IVIG had a larger increase in IgG levels (n = 13, from 7.15 to 8.14 g/L) compared with those previously on SCIG (n = 9, from 8.76 to 8.56 g/L), similarly to children.
A post hoc statistical analysis of the change from baseline in serum IgG trough levels confirmed that IgG levels were maintained in adolescents and adults, and increased in children. For the efficacy period of the study (Infusions 12–17), the mean change from baseline in IgG levels was most pronounced in children (0.920 g/L), with a Hodges–Lehmann point estimate for the change from baseline of 0.680 g/L. The two-sided 95% CI for this change (0.030, 1.500) suggested a significant difference in IgG levels from pre-study level to the level achieved during the efficacy period. The corresponding change from baseline in adolescents and adults indicated stable IgG levels and no significant difference from pre-study to study IgG levels (Table III). Similar results were obtained for the entire study period (Infusions 12–41). A significant increase in IgG levels from baseline was observed in children, while the IgG levels in the other age groups remained stable (Table III).
In a robustness analysis of IgG trough values excluding the seven pediatric patients who had dose adjustments, no relevant difference was observed compared to the analysis for the ITT population.
Nine children and three adolescents participated in the PK substudy. There were no clinically relevant differences between children, adolescents, and adults (n = 11) in the PK parameters for serum IgG.
In children, slightly lower mean values compared to adults were observed for C
max (8.09 vs. 8.31 g/L) and AUC (52.30 vs. 54.52 day × g/L), which was in agreement with the slightly lower mean IgG trough concentrations in children. Corresponding values in adolescents were similar to those in adults (Table II).
Secondary Efficacy Endpoints
Hizentra® was effective in maintaining the rate of infections at a very low level. No SBIs were reported during the efficacy period of the study (Table III). A child with a history of recurrent severe pneumonia experienced an SBI of pneumonia during the wash-in/wash-out period.
Although the annual rate of all infections (including SBIs) in children was slightly lower than in adults (4.77 vs. 5.47 infections per patient per year; Table III), no age-related trends in the incidence of specific types of infection were observed. The most frequent type of infection was cough (seven events in children and six events in adolescents), followed by upper respiratory tract infection (eight events in children and two events in adolescents) and bronchitis (four events in children only).
Eight children missed 139 days from school/day care and three children spent a total of 78 days in hospital (Table III). Of these, the child with recurrent pneumonia missed 71 days from school and spent 63 days in hospital. This child’s experience differed substantially from that of the other patients in the study, regardless of age. Therefore, a post hoc analysis excluding this child was performed to evaluate the efficacy in patients with less severe disease (Table III). In comparison, four adolescents missed only 5 days and none was hospitalized, while eight adults missed 54 days and one adult spent 8 days in hospital. Treatment with antibiotics for prophylaxis or against infections was prescribed to 11 children (442 days) and one adolescent (1 day). The child with recurrent pneumonia was treated for 182 days. Excluding this child, the rate of days on antibiotics in children was twofold lower than the one in adults (Table III).
Safety and Tolerability
Local tolerability results showed that patients tolerated Hizentra® administration well. Children and adolescents experienced 27 and 7 local reactions, respectively (0.040 and 0.035 events per infusion). In children, the most frequent local reactions were infusion site mass (five events), infusion site pruritus (five events), and infusion site pain (four events), followed by infusion site reaction (three events). Adolescents experienced infusion site pruritus (four events), infusion site swelling (two events), and infusion site extravasation (one event). Most of the local reactions were mild in intensity (26 events in children and three in adolescents; Table IV). A total of four moderate local reactions were reported, and only one was severe. Adults reported more local reactions in general, most being mild in intensity (67 of 76 events), yet the rates of moderate local reactions were similar to those in pediatric patients.
Patients or their guardians evaluated the local tolerability as “very good” or “good” for 98.5% of the infusions in children; a rating of “fair” or “poor” was given only for five (0.7%) and two (0.3%) infusions, respectively. In adolescents, local tolerability was rated as “very good” or “good” for 95.5% of the infusions and “fair” for nine (4.5%) infusions. Local tolerability assessments in adults were similar to those in pediatric patients: 95.5% of the infusions were rated as “very good” or “good,” 4.0% as “fair,” and 0.4% as “poor.”
Overall Adverse Events
A summary of all AEs, including local reactions, is provided in Table V.
The rates of AEs, excluding local reactions, were similar in all age groups: 107 AEs occurred during 678 infusions in children (rate 0.158 AEs per infusion) and 41 AEs occurred during 199 infusions in adolescents (rate 0.206 AEs per infusion), compared with 269 AEs during 954 infusions in adults (0.282 AEs per infusion). Excluding local reactions, the most common AEs in children were cough and upper respiratory tract infection (12 and 10 events, respectively; rates 0.018 and 0.015 events per infusion); in adolescents, cough was the most common AE (eight events, rate 0.040).
The rates of temporally associated AEs other than local reactions were somewhat lower in pediatric patients than in adults: 0.090 AEs per infusion in children and 0.085 AEs per infusion in adolescents, compared with 0.148 AEs per infusion in adults. The most common temporally associated AEs were respiratory infections, such as cough, upper respiratory tract infection, and bronchitis.
The frequency of related AEs was lower in children and adolescents than in adults. Excluding local reactions, 20 related AEs were reported in children and four in adolescents (rates 0.029 and 0.020 AEs per infusion, respectively). Excluding local reactions and infections, the most common related AEs in children were pruritus (six events, rate 0.009 events per infusion), erythema (three events, rate 0.004 events per infusion), and psychomotor hyperactivity (three events, rate 0.004 events per infusion). Two related events of headache were reported in children (rate 0.003 events per infusion). In adolescents, the only related AE reported more than once was pruritus (three events, rate 0.015 events per infusion). Adults experienced more related AEs, which were neither local reactions nor infections, the most frequent being headache (11 events, rate 0.012 events per infusion), fatigue (five events, rate 0.005 events per infusion), and pruritus (five events, rate 0.005 events per infusion).
Almost all AEs, excluding local reactions, were mild or moderate in intensity: 95.3% in children and 97.6% in adolescents. Five patients experienced six severe AEs (chest pain, C-reactive protein increased, appendicitis, bronchitis, pneumonia, and cough). In adults, no severe AEs were reported.
Serious Adverse Events and Adverse Events Leading to Discontinuation
No deaths occurred during the study. Serious AEs and AEs leading to discontinuation (all unrelated) were reported only in children.
Three children (16.7%) experienced five SAEs, none of them related to study medication. A 5-year-old girl with a diagnosis of CVID experienced three SAEs: one event of pyrexia and two events of X-ray proven pneumonia. The first event of pneumonia, occurring in the wash-in/wash-out period, was moderate in intensity and was considered an SBI according to the pre-specified FDA criteria because chest X-ray/CT scan showed distinctive nodular and new infiltrative changes in both lungs, despite negative sputum and blood cultures. Approximately a month later, when the patient was hospitalized for diagnostic purposes, bronchoalveolar lavage was positive for atypical mycobacteria in polymerase chain reaction test. Tests for Mycobacterium tuberculosis were negative. With appropriate antibiotic treatment, this SBI resolved after 34 days without sequelae. Four days after Infusion 14, during the efficacy period, the patient experienced pyrexia that was reported as an SAE of moderate intensity; after treatment with antibiotics and ibuprofen, the event resolved after 2 days without sequelae. Four days after Infusion 22, the patient experienced pneumonia that was reported as an SAE of severe intensity. She had fever and cough, and her laboratory tests were indicative of an ongoing inflammatory process (white blood cells 25.69 × 109; C-reactive protein 31.8 mg/L; hemoglobin 9.7 g/dL; ALT 13.1 U/L). Because of the underlying lung disease and medical history of recurrent pneumonia, this event was an acute exacerbation of the existing pneumonia, and thus not considered an additional SBI. The patient completed the study as planned. Two other SAEs—diarrhea (mild) experienced by a 7-year-old girl and appendicitis (severe) experienced by a 10-year-old girl—resolved without sequelae after 2 and 5 days, respectively.
After Infusion 2, an 8-year-old boy with XLA discontinued because of myalgia, pyrexia, and nausea (moderate intensity), and chest pain and C-reactive protein increased (severe intensity). All these AEs were considered unrelated to study medication and resolved without sequelae. The patient was diagnosed with cystic lymphangioma, and thoracic surgery was performed. A 5-year-old boy with XLA discontinued because of anemia of moderate intensity occurring after Infusion 32. The patient had suffered from anemia for 1 year before entering the study and had low hemoglobin values throughout the study (≤10.1 g/dL), as well as abnormally low values for hematocrit, mean corpuscular hemoglobin, mean corpuscular hemoglobin concentration, and mean corpuscular volume at all measurements. The AE was considered unrelated to study medication and was ongoing at final assessment.
Laboratory tests were unremarkable. Median values and ranges of hematology and serum chemistry variables did not show any relevant changes over time. Individual hematology, blood chemistry, and urinalysis values lying outside the normal range were considered by the investigator as not clinically significant in all but two patients. A 10-year-old girl with a history of anemia had low values for hemoglobin, hematocrit, and mean corpuscular volume at most measurements during the study. She was diagnosed with mild iron deficiency anemia that was unrelated to study treatment and resolved without sequelae after 95 days. The 5-year-old boy who discontinued because of anemia had low values for hematocrit, hemoglobin, and several other hematology tests before Infusion 28 and at the completion visit, and a high platelet count at the completion visit.