Patient Disposition and Demographics
Overall, 16 patients were enrolled in the Manual Push Flow Rate Cohort, 14 of whom completed the study (Fig. 1). Two patients (12.5%) discontinued the study at the 1.0-mL/min infusion level; one discontinuation was due to an AE (suicide attempt, unrelated to study drug), and the other was due to a protocol deviation (violation of one of the inclusion criteria: diagnosis of secondary immunodeficiency).
The patient demographics and clinical characteristics of the Manual Push Flow Rate Cohort are presented in Table 1. Mean age was 47.9 years; 15 patients (93.8%) were aged ≥ 18 to ≤ 65 years, and 1 patient (6.3%) was aged 17 years (Table 1). The mean body weight was 81.8 kg. BMI ranged from 19.2 to 40.0 kg/m2, and 7 patients (43.8%) were considered obese (BMI ≥ 30 kg/m2). At study entry, individual patients’ IgPro20 infusion frequency ranged from 2 to 7 infusions per week with volumes of 5–40 mL per infusion.
The percentage of responders at 0.5-, 1.0-, and 2.0-mL/min flow rates was 100%, 100%, and 87.5%, respectively, meeting the prespecified success criterion ≥ 33% for all infusion parameter levels (Fig. 2). The two patients who discontinued at the 1.0-mL/min flow rate met responder criteria for this flow rate. All 14 patients who reached the 2.0-mL/min flow rate were responders at this level. The percentage of valid infusions before non-response was 99.5%, 100%, and 98.5% for the 0.5-, 1.0-, and 2.0-mL/min flow rates, respectively.
For each flow rate level, there were no clinically meaningful differences in the percentage of responders between non-obese and obese patients. Responder rates in obese patients were 100% for all flow rates. In non-obese patients, responder rates were 100% except at the 2.0-mL/min flow rate, which had a 77.8% responder rate due to the 2 patients who discontinued early at the 1.0-mL/min flow rate.
Effect of High Flow Rates on Infusion Time
The mean weekly duration of infusions decreased over time with increasing infusion flow rates (Fig. 3). At the 0.5-mL/min rate, the mean (SD) weekly infusion time ranged from 103 (31.4) to 108 (31.2) min during weeks 1–4, which decreased to 52 (16.9) to 55 (12.9) min at the 1.0-mL/min rate during weeks 5–8, and to 23 (9.8) to 28 (7.8) min at the 2.0-mL/min level during weeks 9–12.
Overall infusion compliance (cumulative actual dose administered/cumulative planned dose) was high for all manual push flow rates, with most patients achieving ≥ 90% compliance (Table 2). In 5 patients, compliance was < 90% at the 0.5- and 1.0-mL/min rates. Two of these patients had missing data records for some infusions at the 0.5-mL/min rate resulting in compliance < 90%. One patient received fewer infusions than planned at the 1.0-mL/min rate to compensate for a higher number of infusions administered at the previous infusion parameter level. Two patients missed doses at the 1.0-mL/min level, because of a natural disaster (n = 1) and for an unknown reason (n = 1). One patient discontinued owing to an unrelated serious AE (suicide attempt) after receiving 5 of 8 planned infusions at the 1.0-mL/min rate. The compliance < 90% at the 0.5- and 1.0-mL/min flow rates did not translate to non-response, as these patients still administered the prespecified minimum number of valid infusions for those flow rates.
Safety and Tolerability
The mean weekly IgPro20 dose administered ranged from 113 to 137 mg/kg over the study duration. Both mean and median IgPro20 volumes and doses were consistent with those planned. The mean (SD) weekly volume (54.9 [15.5] mL) and dose (137.2 [43.0] mg/kg) of IgPro20 were consistent with planned values for the cohort (mean [SD]; planned volume, 54.3 [14.6] mL/week; planned dose, 135.7 [40.0] mg/kg/week). The median volume administered in the cohort was 55.0 mL, and the median dose was 127.3 mg/kg.
Individual median cumulative weekly IgPro20 volumes administered during the study using manual push ranged from 24 to 80 mL, and median cumulative weekly IgPro20 doses ranged from 63 to 211 mg/kg (Fig. 4). As planned, the median (min, max) duration of exposure was 4.00 (2.9, 5.3) weeks at the 0.5-mL/min rate, 4.00 (3.1, 4.6) weeks at the 1.0-mL/min rate, and 4.22 (3.7, 4.7) weeks at the 2.0-mL/min rate.
Overall, including TEAEs occurring after non-response, 12 patients (75.0%) experienced 53 TEAEs across all infusion flow rates, with a rate of 0.085 TEAEs per infusion. A total of 33 TEAEs in 6 patients (37.5%) were considered treatment-related, corresponding to 0.053 related TEAEs per infusion.
TEAEs that occurred under forced upward titration conditions (before non-response) were characterized in more detail. The frequency of TEAEs and the rate of TEAEs per infusion were low and comparable between infusion parameter levels (Table 3). Treatment-related TEAEs were experienced by 3 patients (18.8%), 5 patients (31.3%), and 3 patients (21.4%) at the 0.5-, 1.0-, and 2.0-mL/min flow rates, respectively. Most TEAEs were mild; 3 patients (21.4%) experienced 3 moderate TEAEs at the 2.0-mL/min infusion level. As noted above, only one patient had a serious TEAE (suicide attempt), which was unrelated to treatment and led to study drug discontinuation.
Across all flow rate levels, the most frequent TEAEs were local reactions, all of which were mild. At the 0.5-mL/min flow rate, 5 treatment-related local TEAEs occurred in 2 patients (12.5%), for a rate of 0.023 treatment-related local TEAEs per infusion. The 1.0-mL/min flow rate had the highest frequency of treatment-related local TEAEs, with 17 events occurring in 4 patients (25.0%), for a rate of 0.082 treatment-related local TEAEs per infusion. Finally, 5 treatment-related local TEAEs occurred in 2 patients (14.3%) at the 2.0-mL/min flow rate, resulting in a rate of 0.025 treatment-related local TEAEs per infusion. As there were no severe local reactions, the tolerability was 100% for each flow rate level. No deaths were reported in this study.
Serum IgG Trough Concentrations
The mean (SD) serum IgG trough level in patients at the end of the study (9.58 [2.12] g/L; n = 15) was similar to the baseline IgG trough level in patients on day 1 of the study (9.36 [2.53] g/L; n = 16).