Experience with Subgam, a Subcutaneously Administered Human Normal Immunoglobulin (ClinicalTrials.gov - NCT02247141)

Background and Objectives
A multi-centre, non-comparative study examining the efficacy and safety of Subgam, a normal immunoglobulin (IgG) given weekly as a rapid subcutaneous infusion to patients with primary immune deficiency (PID), is reported. Also included is a summary of adverse drug reactions associated with the use of marketed Subgam in the UK.
Materials and Methods
50 patients with stable PID on IgG therapy were enrolled: Stage 1 included three infusions with prior IgG product followed by 6 months with Subgam, Stage 2 involved long-term Subgam therapy up to 4 years.
Results
Stage 1, 85% of the subjects aged >12 years and 93% of the subjects aged <12 years achieved IgG levels ≥6 and ≥4 g/L, respectively at all observations. There were 3.62 infections/patient/year during Subgam treatment. The most common product-related events were infusion site reactions (50% of patients). Recent post-hoc pharmacokinetics analysis of the post-infusion serum total IgG concentration indicated that the mean dose-normalised incremental IgG AUCτ following intravenous dosing (120.5 g.day/L) was 1.64-fold that of the dose-normalised mean incremental IgG AUCτ following subcutaneous dosing (73.6 g.day/L), corresponding to an estimated IgG bioavailability for subcutaneous dosing of 61%. Only 34 post-licensing adverse reactions have been received in 30 patients over a period of 10 years; fourteen were classed as serious as defined by the ICH guidelines on good clinical practice. The most common post-licensing adverse reaction was infusion site reaction (7 reports). There were 7 reports of flu-like symptoms (pyrexia/shivering/rigors/feeling hot or cold), 2 other reports of combined flu-like symptoms and infusion site reactions, 5 reports of generalised skin reactions, and 3 reports of combined infusion site and skin reactions. There were also reports of anaphylaxis (2 reports) and 8 other adverse events (including headache). In conclusion, Subgam is effective and well tolerated in the treatment of PID.
Trial Registration
ClinicalTrials.gov NCT02247141

研究背景与目的
本研究为一项多中心非对照试验，旨在考察Subgam——一种正常免疫球蛋白（IgG）——作为快速皮下输注制剂，每周给药一次用于原发性免疫缺陷病（PID）患者的有效性与安全性。同时本研究亦汇总了英国境内上市的Subgam相关药品不良反应数据。

材料与方法
本研究共纳入50例病情稳定且接受IgG治疗的原发性免疫缺陷病患者：第一阶段为3次输注既往使用的IgG制剂，随后接受6个月Subgam治疗；第二阶段为最长达4年的长期Subgam维持治疗。

研究结果
第一阶段中，所有随访时点下，年龄＞12岁受试者中有85%、年龄＜12岁受试者中有93%的IgG水平分别达到≥6 g/L与≥4 g/L。Subgam治疗期间，患者年感染率为3.62次。最常见的药物相关不良事件为输注部位反应（占受试患者总数的50%）。
近期开展的事后药代动力学分析显示，静脉输注后的剂量标准化增量IgG曲线下面积（AUCτ）均值为120.5 g·day/L，约为皮下输注后剂量标准化增量IgG AUCτ均值（73.6 g·day/L）的1.64倍，据此估算皮下输注的IgG生物利用度为61%。
10年间共收到30例患者上报的34例上市后不良反应；其中14例符合国际人用药品注册技术协调会（ICH）药物临床试验质量管理规范指南定义的严重不良反应范畴。最常见的上市后不良反应为输注部位反应（7例报告）。另有7例报告类流感症状（发热/寒战/僵直/冷热感异常）、2例报告类流感症状合并输注部位反应、5例报告全身性皮肤反应、3例报告输注部位反应合并皮肤反应。此外还有2例过敏性休克报告及8例其他不良事件报告（包括头痛）。
综上，Subgam用于原发性免疫缺陷病的治疗安全有效且耐受性良好。

试验注册
临床试验注册平台（ClinicalTrials.gov）编号：NCT02247141