Participants

Overall, 44 participants were enrolled; 34 participants completed the study with 10 participants prematurely discontinuing (Fig. 2). The overall mean (range) study duration was 14.1 (0.7–38.7) months.

Fig. 2

Participant disposition. aAll participants who provided informed consent. bAll participants who provided informed consent and met enrollment eligibility. cA COVID-19-related constraint at the study site resulted in the participant being unable to complete the final study visit

In total, 43 participants completed Epoch 1 and entered Epoch 2; one participant prematurely discontinued Epoch 1 owing to an AE (worsening of pre-existing celiac disease). Of the 43 participants who entered Epoch 2, nine prematurely discontinued owing to withdrawal by the participant (n = 6; participants were free to withdraw from the study at any time without obligation to provide a reason for their decision), an AE (n = 1; infusion site pain), physician decision (n = 1), and for reasons related to COVID-19 (n = 1) (Fig. 2).

Baseline characteristics of the study population are summarized in Table 2. Mean ± standard deviation (SD) (median [range]) age of the study population was 9.0 ± 3.6 (9.5 [3–15]) years, with most participants (n = 23; 52.3%) in the 6 to < 12-year age group. Common variable immunodeficiency was the most common PIDD diagnosis at baseline (40.9%), followed by specific antibody deficiency (36.4%). Specific antibody deficiency was the most common diagnosis among participants aged 2 to < 6 years (77.8%), whereas common variable immunodeficiency was the most frequently reported diagnosis for those aged 6 to < 12 years (47.8%) and 12 to < 16 years (50.0%).

Table 2 Baseline characteristicsAcute Serious Bacterial Infections (ASBIs)

Two ASBIs, both cases of bacterial pneumonia, occurred in one participant (2.3%) with a diagnosis of specific antibody deficiency (normal immunoglobulin concentration and number of B cells). The first ASBI occurred during Epoch 1 and the second during Epoch 2; both events were not temporally associated with the last infusion received, occurring after more than 72 h from the last infusion. Past medical history for the participant included bronchiolitis, respiratory syncytial virus infection, gastroesophageal reflux disease, and tracheomalacia.

The mean rate of ASBIs was 0.04 per participant-year (99% upper CI: 0.20), significantly (p < 0.001) lower than the regulatory-defined threshold rate of 1.0 [17]. Therefore, the primary endpoint of the study was met.

All Infections

Overall, 161 infections were experienced by 34 participants (77.3%), equivalent to a mean rate of 3.12 events per participant-year (95% upper CI limit: 3.95). Mean infection rates per participant-year by age group were 4.01, 3.23, and 1.97 for the 2 to < 6, 6 to < 12, and 12 to < 16-year age groups, respectively. All infections occurring in at least one participant with an infectious event are reported in Supplementary Table S1. The most commonly reported infections (occurring in > 10% of participants) by preferred term across the entire study were as follows: sinusitis (including preferred terms for sinusitis and acute sinusitis: 32 events in 23 participants [52.3%]), upper respiratory tract infection (URTI; including preferred terms for URTI and viral URTI: 24 events in 18 participants [40.9%]), streptococcal pharyngitis (11 events in 7 participants [15.9%]), influenza (6 events in 6 participants [13.6%]), and otitis media (including preferred terms for acute otitis media and chronic otitis media: 16 events in 8 participants [18.2%]).

Treatment Characteristics

The overall mean ± SD duration of exposure to fSCIG 10% during the study was 14.0 ± 5.4 months (Epoch 1: 1.3 ± 0.3 months; Epoch 2: 13.0 ± 5.1 months).

In Epoch 2, 633 infusions were administered (145, 339, and 149 infusions in the 2 to < 6, 6 to < 12, and 12 to < 16-year age groups, respectively). Treatment characteristics for infusions administered during Epoch 2 are summarized in Table 3. Across all age groups, participants received a median (range) of 1.1 (1.0–1.5) infusions per month. The median (range) number of infusions per participant-year was 13.2 (11.5–17.7). Overall, the median (range) number of infusion sites per month was 2.2 (1.1–2.9), with similar median values across age groups. The mean ± SD number of infusion sites per infusion was 1.8 ± 0.4 and the median (range) was 2.0 (1.0–2.0), which were comparable across age groups. The overall median (range) duration of infusion was 85 (45–215) minutes. The median (range) infusion volume was 85 (35–300) mL/site, and was lowest in the 2 to < 6-year age group (60.0 mL/site) and highest in the 12 to < 16-year age group (142.5 mL/site), with a maximum (range) infusion rate of 160 (30–300) mL/hour/site. The first 2–3 infusions during Epoch 2 were mandatorily administered at study sites; thereafter 74.4% of participants received ≥ 2 infusions at home and 45.3% of all infusions during Epoch 2 were administered in the home setting.

Table 3 Treatment characteristics for fSCIG 10% in Epoch 2Serum IgG Trough Levels

Mean ± SD (median [range]) serum total IgG levels at baseline were similar between participants previously receiving IVIG and SCIG (9.8 ± 1.9 [10.5 (6.1–11.1)] and 10.1 ± 3.2 [9.3 (4.6–24.4)] g/L, respectively). For the overall study population, mean ± SD (median [range]) serum IgG trough levels were 10.38 ± 2.91 (10.05 [4.46–22.90]), 9.20 ± 1.96 (9.42 [3.04–13.10]), and 9.21 ± 1.98 (9.29 [4.02–14.10]) g/L at Months 0, 6, and 12, respectively, of Epoch 2. IgG trough levels stayed stable between visits (Table 4). In addition, serum IgG trough levels were generally similar across age groups, although participants in the 2 to < 6-year age group had slightly lower levels compared with other age groups. Additionally, mean serum total IgG concentration profiles were similar for each age group (Fig. 3).

Table 4 IgG trough levels during Epoch 2 in the full analysis setFig. 3

Box plots of serum trough levels of total IgG by visit and age group. Age group is based on participant age at screening. The length of a box represents the IQR. The dashed line in the box indicates the group mean, and the horizontal line reflects the group median. The vertical lines issuing from the box extend to the group minimum (Q1 − 1.5 × IQR) and maximum (Q3 + 1.5 × IQR) values. Outliers are shown as circles. IgG, immunoglobulin G; IQR, interquartile range; Q, quartile

Safety and TolerabilityAdverse Events

Excluding infections, 536 treatment-emergent AEs (TEAEs) were recorded by 43 participants, of which 336 events in 34 participants were considered treatment-related with the vast majority of these mild in nature (Table 5). The most common TEAEs (excluding infections) were infusion/injection site pain (52.3% of participants), headache (43.2%), and infusion/injection site pruritus (29.5%) (Table 6). The overall rate of treatment-related TEAEs (excluding infections) was 0.443 events per infusion. This rate decreased over time from Epoch 1 (0.675 events/infusion) to Epoch 2 (0.397 events/infusion) (Table 5). Most treatment-related TEAEs were mild (247 events [73.5% of related TEAEs]) or moderate (87 events [25.9%]) in severity, and were reported in 32 participants (72.7%) and 19 participants (43.2%), respectively. Three severe AEs (excluding infections), all of which were systemic, were reported in three participants; two of the severe AEs were assessed as treatment-related (celiac disease flare and headache). One serious AE (excluding infections) was reported (tonsillar hypertrophy) but was not considered to be treatment-related. The overall rate of treatment-related systemic and local TEAEs (excluding infections) were 0.190 and 0.253 events per infusion, respectively, and decreased over time from Epoch 1 (systemic, 0.214; local, 0.460) to Epoch 2 (systemic, 0.185; local, 0.212) (Table 5). A summary of TEAEs including infections is presented in Supplementary Table S2.

Table 5 Summary of TEAEs, excluding infections, by epoch and overall in the safety analysis setTable 6 Summary of the most common TEAEs, excluding infections (occurring in ≥ 10% of participants) in Epochs 1 and 2 combined (N = 44 participants)

The overall rates of any TEAEs (excluding infections) per infusion and per participant were 0.706 and 12.182, respectively, equivalent to a rate of 10.375 events per participant-year. These rates declined over time from Epoch 1 to Epoch 2. Thus, in Epoch 1, the equivalent rates were 0.944 and 2.705 with a rate of 25.719 events per participant-year. For Epoch 2, the corresponding rates were 0.659 and 9.698 with a rate of 8.865 events per participant-year. The proportion of participants with any local TEAE was also highest at the start of treatment and decreased rapidly over the first 120 days and had further decreased by Day 450 (Fig. 4). After Day 630, only one participant was still receiving treatment; the participant was observed for up to 1200 days and reported two TEAEs during this time.

Fig. 4

Frequency of local TEAEs over time. The x axis represents time intervals for each month (30 days). The first bar is the proportion of participants with a TEAE that started between Day 1 and Day 30, the second bar is the proportion of participants with a TEAE that started between Day 31 and Day 60, and so on. The proportion was computed as follows: 100 × (number of participants with an event/number of participants at risk for an event in that time period). One participant was observed for up to 1200 days and experienced two TEAEs (not shown). TEAE, treatment-emergent adverse event

Overall, 13 participants (30.2%) had 17 infusions that were interrupted owing to an AE (2.7% of infusions administered in Epoch 2; Table 3), and the proportion of patients with interruptions was broadly similar across the three age groups evaluated (33.3%, 27.3%, and 33.3% in the 2 to < 6, 6 to < 12, and 12 to < 16-year age groups, respectively). AEs that contributed to interruption of infusion (alone or in combination) included infusion site extravasation, erythema, swelling, pain and pruritus, and dizziness. Of all infusions administered over the course of the study, 99.8% were completed; 94.1% were completed without interruption.

Binding and Neutralizing Antibodies against rHuPH20

One participant with specific antibody deficiency developed an anti-rHuPH20 binding antibody titer ≥ 1:160 rHuPH20 at Month 6 of Epoch 2 (titer, 1:640). At Months 9, 12, and 15 of Epoch 2, anti-rHuPH20 binding antibody titers were 1:1280, 1:2560, and 1:2560, respectively, followed by titers of 1:10,240 (Month 18), 1:2560 (Month 21), 1:5120 (Month 24), and 1:10,240 (Month 27). Titers then decreased to 1:2560 (Month 30, unscheduled visit) and were at 1:5120 by the end of the study (Epoch 2, Month 36). The participant experienced local and systemic TEAEs (mostly headache) before and after developing anti-rHuPH20 binding antibodies. All treatment-related TEAEs in this participant fully resolved without sequelae and none were considered serious or severe, or considered to be a result of an immune-mediated response. Additional characterization of antibodies in this participant determined that they did not contain antibodies cross-reacting with Hyal 1, 2, and 4, and there was no evidence of complement consumption or immune complex formation. Total IgG trough levels for this participant remained stable throughout Epoch 2, and there was no association between maximum IgG concentration and rHuPH20-reactive antibodies. The overall incidence of treatment-emergent anti-rHuPH20 binding antibodies was 2.3% (1/44 participants). No rHuPH20 neutralizing antibodies were detected in any participant.

Participant-Reported OutcomesHealth-Related Quality of Life

At the end of Epoch 2, mean ± SD changes from baseline in the Pediatric Quality of Life Inventory (PedsQL) total score were small in magnitude and similar across age groups: 8.2 ± 17.7, − 4.6 ± 16.3, − 2.0 ± 14.0, and − 2.5 ± 8.8 for participants in the 2–4, 5–7, 8–12, and 13–< 16-year age groups, respectively. Given the small sample size in each group, these data should be interpreted with caution.

Treatment Preference

At the end of Epoch 2, positive responses were recorded by most participants who completed the treatment preference questionnaire (n = 42). The highest-rated aspects of treatment were frequency of administration and overall convenience; 88% and 81% of respondents, respectively, rated these aspects as “liked very much” or “liked”. Most participants also expressed a preference for continuing fSCIG 10% (74%) and for receiving treatment at home (86%).

Healthcare Resource Utilization

The median (range) number of days wherein a participant was not able to go to school/work or to perform normal daily activities due to infection or other illness was 1.5 (0–51) days per participant. This equated to a mean rate of 4.28 (standard error [SE]: 1.00) (95% CI: 2.71–6.75) days per participant-year.

In total, 28 participants (63.6%) received antibiotics during the study, with a median (range) per participant of 3.0 (1.0–11.0) courses and 34.5 (5.0–343.0) days on treatment during the study. This equated to a mean (SE) rate per participant-year of 2.2 (0.4) antibiotic courses and 26.8 (5.5) days on antibiotic treatment.

Four participants were hospitalized. The mean rate of infection-related hospitalizations was 0.06 (SE: 0.03) (95% CI: 0.02–0.18) per participant-year; the median (range) number of infection-related hospitalizations per participant was 0.0 (0.0–1.0). The median (range) number of days hospitalized per participant was 0.0 (0.0–4.0), with a mean rate of 0.21 (SE: 0.07) (95% CI: 0.11–0.42) days hospitalized per participant-year.