Aim: This post hoc analysis evaluated the efficacy and overall tolerability of immunoglobulin (Ig) treatment modalities (intravenous Ig [iv.Ig], subcutaneous Ig [sc.Ig] and facilitated sc.Ig [fsc.Ig]). Materials & methods: A total of 30 participants with primary immunodeficiency diseases aged ≥2 years sequentially received iv.Ig, sc.Ig and fsc.Ig during consecutive clinical studies. Results: For iv.Ig, sc.Ig and fsc.Ig, rates of validated acute serious bacterial infections/participant-year (0, 0.09 and 0.04, respectively) and all infections/participant year (4.17, 3.68 and 2.42, respectively) were similarly low; rates of systemic and local causally related adverse events/participant-year were 5.60, 1.93 and 0.88, respectively and 0.13, 0.92 and 1.57, respectively. Conclusion: fsc.Ig provided similar efficacy to iv.Ig and sc.Ig. Clinical Trial registration: NCT00546871, NCT00814320, NCT01175213 (ClinicalTrials.gov).

Immune globulin subcutaneous, human – klhw 20% solution (IGSC-C 20%) is a new treatment for patients with PI. The primary objective determined whether the pharmacokinetics (PK) of IGSC-C 20% is noninferior to intravenous (IV) immune globulin injection (human),10% caprylate/chromatography purified (IGIV-C 10%). This study included participants, aged 2–72 years with PI (n=53). Participants received IGIV-C 10% during the Run-in Phase (n=44) prior to IV PK profiling or entered the IV Phase directly (n=9), then switched to weekly infusions of IGSC-C 20% (n=49) for approximately 24 weeks at a dose adjustment factor (DAF) of 1.37. The primary (PK IgG) and exploratory (infection rates and pathogen antibody titers) endpoints were assessed. Steady state IgG trough concentration was 1.333-fold higher with IGSC-C 20% (∼1245 mg/dL) than IGIV-C 10% (∼957 mg/dL). The geometric least-squares means ratio of the area-under-the-curve for IGSC-C 20% (n=39) vs IGIV-C 10% (n=49) was 104% (90% CI: 100%–107%). IGIV-C 10% rose rapidly to 2075 (range: 1350–3000) mg/dL IgG followed by a decline; IGSC-C 20% postinfusion remained stable between 1263 mg/dL and 1358 mg/dL through 7 days. The rates of serious bacterial infections per subject-year was 0.049 (95% CI: 0.020-0.098; upper 99% CL: 0.110) with IGSC-C 20% and 0.120 (0.051-0.232; 0.259) with IGIV-C 10%. Infection rates and trough pathogen antibody titers were comparable between treatments. IGSC-C 20% (at DAF of 1.37) provided noninferior and bioequivalent IgG exposure to IGIV-C 10%, with 33% higher mean IgG trough values, and less fluctuations in IgG concentrations.

This trial assessed the safety and tolerability of IGSC-C 20% and intravenous immune globulin infusion (human),10% caprylate/chromatography purified (IGIV-C 10%) in participants with PI. There were 3 phases: Run-in (IGIV-C 10%, n=44), IV (IGIV-C 10%, n=52 [9 entered without Run-in]), and SC (weekly IGSC-C 20%, dose adjustment factor of 1.37, n=49). Safety analyses were performed. Local infusion site reactions (ISRs) were considered adverse events (AEs) when signs/symptoms led to infusion interruption/discontinuation, required concomitant medication, or impacted the general condition of the participants. Of the 261 IGIV-C 10% and 1053 IGSC-C 20% infusions, 99.7% completed without interruption. Most IGSC-C 20% infusions used 2 (30.5%) or 4 (56.2%) infusion sites. During the Run-in+IV phases, 33 participants reported 79 AEs. Forty-one participants reported 141 AEs during the SC phase. Most (>96%) AEs were mild to moderate in severity. One participant reported 2 serious AEs (SAEs) in the Run-in+IV phases and 2 in the SC phase reported 4 SAEs; all unrelated to study drug. Rates of potentially related AEs (PRAEs) per infusion were 0.050 in Run-in+IV and 0.058 in SC phases. Headache was the most frequent PRAEs in the Run-in+IV phases (3.8%, 0.008 event/infusion); whereas, 1 participant (2.0%, 0.001 event/infusion) in SC Phase experienced headache. The majority (98.3%) of PRAEs in the SC phase were mild or moderate in severity, primarily local ISRs. There were no treatment-emergent fatigue or nausea, thromboembolic AEs, or death during this study. IGSC-C 20% is well tolerated and has a safety profile similar to IGIV-C 10% in this study.

Aim: This prospective, Phase III study assessed the pharmacokinetics (PK), safety and tolerability of immune globulin subcutaneous, human - klhw 20% solution (IGSC-C 20%) in participants with primary humoral immunodeficiency (PI), compared with immune globulin injection (human), 10% caprylate/chromatography purified (IGIV-C 10%). Patients & methods: About 53 participants enrolled. Total 44 received IGIV-C 10% in the run-in phase and then entered the IV phase (with an additional nine who were already receiving IGIV-C 10% and entered the IV phase directly) for steady-state IV PK assessments. Total 49 entered the SC phase (weekly doses of IGSC-C 20% for ∼24 weeks). The PK profiles of IGIV-C 10% and IGSC-C 20% and their safety and tolerability parameters were compared. Results: At a dose adjustment factor of 1.37, IGSC-C 20% provided comparable (noninferior and bioequivalent) overall total immunoglobulin G exposure to IGIV-C 10% over an equal time interval. About 33 participants reported 79 adverse events during run-in + IV phases; 41 participants reported 141 adverse events during the SC phase, with most being local infusion site reactions. The majority of infusion site reactions were mild to moderate in severity. Conclusion: IGSC-C 20% was bioequivalent to IGIV-C 10% and was well tolerated, with a safety profile comparable with IGIV-C 10%, in this study. Trial registration: ClinicalTrials.gov identifier: NCT02604810.

Background: The subcutaneous immune globulin (SCIG) 20% product, Ig20Gly, was shown to be efficacious and well tolerated in 2 phase 2/3 North American and European studies at infusion volumes up to 60 mL/site and rates up to 60 mL/h/site in patients with primary immunodeficiency diseases. Objective: To assess patient experience after switching to Ig20Gly with fast infusion rates and large infusion volumes/site in the North American study. Methods: In this analysis of the open-label phase 2/3 study in which patients aged >= 2 years received weekly Ig20Gly infusions for up to approximately 1.3 years, tolerability and infusion parameters were assessed throughout the study for all patients and by prestudy treatment regimen (intravenous [IV] switchers or SC switchers). Results: Overall, 61% of patients reached the infusion rate of >= 60 mL/h/site and continued at this rate for 1 or more subsequent infusions; the median infusion number when patients first reached >= 60 mL/h/site was 3. No association was found between higher infusion volumes or rates and increased incidences of local and systemic adverse events (AEs) in the total population and patients younger than 16 years. Infusion parameters and tolerability were generally comparable regardless of the route of prestudy treatment (IV or SC switchers); however, IV switchers experienced lower rates of local AEs than SC switchers and had a slightly higher median infusion volume per site and longer infusion duration vs SC switchers. Conclusion: High Ig20Gly infusion rates of at least 60 mL/h/site and volumes >= 60 mL/site were well tolerated during onboarding and throughout treatment, regardless of prestudy treatment. (C) 2019 American College of Allergy, Asthma & Immunology.

Aim: This pooled analysis evaluated the safety and tolerability of the subcutaneous immunoglobulin 20% product, Ig20Gly, in primary immunodeficiency diseases using data from two Phase II/III studies conducted in North America and Europe. Patients & materials/methods: Patients received Ig20Gly (volumes, ≤60 ml/site; rates, ≤60 ml/h/site). Adverse events (AEs), tolerability and infusion parameters were assessed. Results: Patients (2-83 years; N = 122) received 6676 Ig20Gly infusions. No causally related serious or severe AEs were reported. Thirty-five patients (28.7%) reported 232 causally related local AEs. Twenty-seven patients (22.1%) reported 165 causally related systemic AEs. There was no association between the infusion volume or rate and causally related local AEs. Conclusion: Ig20Gly was well tolerated in a broad population of patients with primary immunodeficiency diseases.

Background: Recombinant human hyaluronidase (rHuPH20)-facilitated subcutaneous infusion of immunoglobulin (fSCIG; HyQvia) is a new Ig treatment combining the advantages of intravenously and conventional subcutaneously-administered immunoglobulin (Ig) with infusion at rates, volumes and frequencies similar to intravenous Ig (IVIG), and favorable systemic tolerability. Objectives: We report the efficacy, adverse events, and tolerability of fSCIG in patients aged < 18 years treated in the pivotal phase 3 study and its extension. Methods: Patients aged < 18 years with PID received IVIG for 3 months, then fSCIG every 3 or 4 weeks for ~18 months, followed by up to 21 months. Results: Of the 26 enrolled patients (aged 4-17 years), 24 received fSCIG for up to 3.3 years at the established dose (49 patient-years). No serious fSCIG-related adverse events were reported. The rate of validated acute serious bacterial infections was 0.08/patient-year (upper limit of 99 % CI = 0.20) and the rate of all infections with fSCIG was 3.02/patient-year. The rate of related local adverse events was 0.10/infusion; results were similar when stratified by age group or maximum infusion volume/site. Of 706 fSCIG infusions, 97 % did not require administration changes. Three patients developed binding anti-rHuPH20 antibody at titers ≥ 1:160 on ≥ 1 occasion with no associated adverse reactions; titers declined, despite continued treatment. No patient developed neutralizing anti-rHuPH20 antibodies. Conclusions: In patients aged < 18 years who were treated with fSCIG, infection rates were low, and infusions were well-tolerated, despite infusion volumes and rates like IVIG. The results in pediatric patients were like those in adults.

Subcutaneous immune globulin (SCIG) 20%, Ig20Gly (Cuvitru®), was safe and efficacious in a phase 2/3 North American study (NCT01218438) in patients with primary immunodeficiency diseases (PIDD). This post hoc analysis assessed the onboarding experience with Ig20Gly by examining infusion parameters based on prestudy treatment (intravenous IG [IVIG] or SCIG). Patients aged ≥2 years who were treated with IVIG (IV-switchers) or SCIG (SC-switchers) immediately before study entry received Gammagard Liquid (IVIG10%) at the monthly dose equivalent to their recent prestudy treatment for 3 months. All patients were then switched to once-weekly Ig20Gly for ∼1 year. Infusion rates of ≥60 mL/h/site for more than one infusion were reached by 58.8% (30/51) of IV-switchers and 65.2% (15/23) of SC-switchers; the median infusion number when patients first reached 60 mL/h/site was 3 for both groups. Infusions were completed in <1 or 1–2 hours in 41.8% and 50.9% of 2784 infusions in IV-switchers and 75.8% and 19.9% of 1378 infusions in SC-switchers, respectively (median infusion duration, 1.07 hour [IV-switchers] and 0.82 hour [SC-switchers]). IV-switchers administered 63.7% (450/706) of infusions with dose volumes of 0–59 mL using 1 infusion site; whereas SC-switchers administered 45.7% (307/672) of infusions with dose volumes of 0–59 mL using 1 infusion site. IV-switchers and SC-switchers administered 84.2% (1525/1812) and 72.7% (482/663) of infusions with dose volumes of 60–119 using 2 infusion sites, respectively. Comparable Ig20Gly infusion rates but higher infusion durations and lower number of infusion sites by volume were observed for patients who previously received IVIG versus SCIG.

Cuvitru, a new human immune globulin (Ig) subcutaneous, 20% (SCIG 20%) ready-for-use, liquid preparation of highly purified human IgG, was well tolerated based on data from a combined analysis of two phase 2/3 studies in patients with primary immunodeficiency diseases (PIDD) in Europe and North America. Improved tolerability of this new SCIG 20% allows for increased dose/site (up to 12 g/site) and fast infusion rates (up to 60 mL/hr/site), while demonstrating a low rate of local adverse reactions (LARs). The rate of LARs was assessed in patients with PIDD aged ≥2 years, who at screening were receiving Ig replacement therapy (300-1000 mg/kg every 3-4 weeks) ≥3 months and had a serum IgG trough level of >500 mg/dL. Overall, 112 (91.8%) of 122 patients aged 2-83 years who were treated with SCIG 20% completed the studies (median of 365 days). Only one discontinuation was due to mild infusion-site pain. The LAR rate was 0.034/infusion; almost all were mild (0.033/infusion) and 0.001/infusion were moderate in severity. No treatment-related LARs were reported in 65.6% (80/122) of patients; 3.1% of infusion were associated with non-serious LARs. Most infusions were completed in <1 hour (n=3,445; 53%) or <2 hours (n=6,005; 92.4%). Overall, 99.8% of 6,665 infusions were completed without any administration changes, such as slowing, interrupting, or stopping the infusion. A positive safety and tolerability profile of a new SCIG 20% was demonstrated in patients with PIDD at increased doses/site, large infusion volumes/site, and relatively fast infusion rates.

In the recent letter to the editor, BAssessment of Local Adverse Reactions to Subcutaneous Immunoglobulin (SCIG) in Clinical Trials^[1], Ballow et al. discuss the inappropriateness of making comparisons of adverse event (AE) and tolerability data from different clinical trials of subcutaneous immunoglobulins (IGs) unless the products are studied contemporaneously within the same study using the same methodology, the same investigators, and the same patient populations.The authors conclude that Bgiven the current difficulties in standardizing methodologies across sites and studies, comparisons of tolerability of different products in reported clinical trials should be avoided.^Theirletter focuses on the recent phase 3 clinical trial publication of IG20Gly (Cuvitru®, SCIG 20%,

Gammaplex 10% is a new, ready-prepared IVIG. A recent clinical trial established the bioequivalence of the Gammaplex 10% and 5% formulations. Here we compare the infusion durations and related tolerability of the two formulations administered using 15-minute titration periods. GMX07 (NCT01963143) was a phase 3, multicenter, open-label, randomized, 2-period, crossover bioequivalence trial that evaluated the pharmacokinetics, safety, and tolerability of Gammaplex 10% in adult and pediatric patients with primary immunodeficiency diseases. Bioequivalence of Gammaplex 10% and Gammaplex 5% was assessed in adults. For each infusion, the infusion rate was increased at 15-minute intervals depending on subjects' tolerability. The median infusion duration for Gammaplex 10% (n=32) was 108.5 min (range 66-252), compared with 161 min (range 75-348) for Gammaplex 5% (n=33). Of subjects receiving Gammaplex 10% and 5% infusions, 96% and 94%, respectively, reached and were maintained at the highest infusion rate. Of 166 Gammaplex 10% infusions, 27 (16.3%) were temporally associated with ≥1 product-related adverse event (AE) versus 32 of 163 (19.6%) Gammaplex 5% infusions. The most common (≥5% in either group) product-related AEs reported during or within 1 hour of infusions' end were headache (9.4% [Gammaplex 10%] vs 15.2% [Gammaplex 5%]), migraine (0% vs 6.1%), pyrexia (6.3% vs 0%), and fatigue (3.1% vs 6.1%). Gammaplex 10%, the first 10% IVIG with a 15-minute titration schedule, allows shorter infusion durations than a 5% IVIG product, with a similar tolerability profile.

This phase 3, multicenter, open-label, randomized, two-period, crossover bioequivalence trial evaluated the safety, tolerability, and pharmacokinetics of intravenous immunoglobulins (IVIGs) Gammaplex 5% and Gammaplex 10% in 33 adults and 15 children with primary immunodeficiency diseases (PIDs).

Data from a phase 2/3 North American clinical trial provided an opportunity to understand the onboarding experience of a new SCIG 20% in patients with PIDD. This new highly-concentrated SCIG 20% allows for fast infusion rates and large infusion volumes resulting in shorter infusion durations. Patients (3-83 years) received weekly SCIG 20% for ∼1.3 years. As tolerated, volumes up to 60 mL/site and rates up to 60 mL/hr/site were infused. Associations between the rate of causally-related local AEs and the infusion parameters were investigated. Of the 77 enrolled patients, 53 (69%) had no previous SCIG-experience. Overall, 91% (67/74) of patients treated with SCIG 20% completed the study; none of the discontinuations (n=7) were due to treatment-related systemic or local AEs. There was no association between the rates of causally-related local AEs (0.4%, 1.4%, 1.1%, and 0.3%, respectively) and the infusion volume/site (30-39, 40-49, 50-59, and ≥60 mL/site, respectively). At infusion 1, 13% of patients reported ≥1 causally-related local AEs, which decreased and remained low throughout the study. The median total infusion time was 0.95 hours (53% and 94% of infusions were delivered in <1 and <2.0 hours, respectively). The median maximum infusion rate (60 mL/hr/site) was used by 71.6% (53/74) of patients and during 57.3% of infusions. The percent of patients who experienced causally-related local AEs during onboarding was low, which decreased and remained low over time. The rate of local AEs was not associated with fast infusion rates or large volumes per site with this new SCIG 20% treatment.

Ig therapies for PIDD are available in different administration modes, characterized by their pharmacokinetics, infusion parameters, and tolerability. We report the efficacy and tolerability data for a subset of 31 patients with PIDD who switched modes of Ig therapy during three consecutive studies. In Study 1, patients received IVIG 10% every 3-4 weeks (≥3 months), followed by weekly SCIG 10% (≥12 months; mean 137% of IV dose); in Study 2, they were switched to recombinant hyaluronidase-facilitated SCIG 10% (IGHy) (mean 108% of IV dose) every 3-4 weeks for ∼14-18 months; then, in Study 3 (extension of Study 2), they continued with the same IGHy dose for up to 48 weeks (exposure=122.5 patient-years). Longitudinally across three consecutive studies, the annual rate of validated acute bacterial infections (VASBIs) and all infections were low: IVIG (0.00/4.04), SCIG (0.09/3.93), and IGHy (0.04/2.4) (rate of VASBIs/all infections, respectively). The rate of causally-related AEs/patient-year was lower for IGHy (2.44) compared with IVIG (4.17) or SCIG (2.77). The rate of causally-related systemic AEs/patient-year was highest in patients receiving IVIG (5.60) (IGHy [1.90]; SCIG [1.88]). The rate of local AEs/patient-year was lowest for IVIG (0.13) (SCIG [0.90]; IGHy [1.56]). Median IgG trough levels (g/L) were similar for IVIG (10.4), SCIG (13.1), and IGHy (9.9). Long-term evaluation of the same patient cohort over three consecutive studies demonstrated that IGHy, compared to the other modes of Ig therapy patients received prior to initiating IGHy provided similar efficacy, and safety and tolerability profiles. IgG trough levels were maintained throughout the studies.