Uppsala University Hospital, Uppsala, Sweden.
University of Leicester, Leicester, UK.
Lancet. 2017 May 27;389(10084):2117-2127. doi: 10.1016/S0140-6736(17)30550-0. Epub 2017 Mar 28.
IgA nephropathy is thought to be associated with mucosal immune system dysfunction, which manifests as renal IgA deposition that leads to impairment and end-stage renal disease in 20-40% of patients within 10-20 years. In this trial (NEFIGAN) we aimed to assess safety and efficacy of a novel targeted-release formulation of budesonide (TRF-budesonide), designed to deliver the drug to the distal ileum in patients with IgA nephropathy.
We did a randomised, double-blind, placebo-controlled phase 2b trial, comprised of 6-month run-in, 9-month treatment, and 3-month follow-up phases at 62 nephrology clinics across ten European countries. We recruited patients aged at least 18 years with biopsy-confirmed primary IgA nephropathy and persistent proteinuria despite optimised renin-angiotensin system (RAS) blockade. We randomly allocated patients with a computer algorithm, with a fixed block size of three, in a 1:1:1 ratio to 16 mg/day TRF-budesonide, 8 mg/day TRF-budesonide, or placebo, stratified by baseline urine protein creatinine ratio (UPCR). Patients self-administered masked capsules, once daily, 1 h before breakfast during the treatment phase. All patients continued optimised RAS blockade treatment throughout the trial. Our primary outcome was mean change from baseline in UPCR for the 9-month treatment phase, which was assessed in the full analysis set, defined as all randomised patients who took at least one dose of trial medication and had at least one post-dose efficacy measurement. Safety was assessed in all patients who received the intervention. This trial is registered with ClinicalTrials.gov, number NCT01738035.
Between Dec 11, 2012, and June 25, 2015, 150 randomised patients were treated (safety set) and 149 patients were eligible for the full analysis set. Overall, at 9 months TRF-budesonide (16 mg/day plus 8 mg/day) was associated with a 24·4% (SEM 7·7%) decrease from baseline in mean UPCR (change in UPCR vs placebo 0·74; 95% CI 0·59-0·94; p=0·0066). At 9 months, mean UPCR had decreased by 27·3% in 48 patients who received 16 mg/day (0·71; 0·53-0·94; p=0·0092) and 21·5% in the 51 patients who received 8 mg/day (0·76; 0·58-1·01; p=0·0290); 50 patients who received placebo had an increase in mean UPCR of 2·7%. The effect was sustained throughout followup. Incidence of adverse events was similar in all groups (43 [88%] of 49 in the TRF-budesonide 16 mg/day group, 48 [94%] of 51 in the TRF-budesonide 8 mg/day, and 42 [84%] of 50 controls). Two of 13 serious adverse events were possibly associated with TRF-budesonide-deep vein thrombosis (16 mg/day) and unexplained deterioration in renal function in follow-up (patients were tapered from 16 mg/day to 8 mg/day over 2 weeks and follow-up was assessed 4 weeks later).
TRF-budesonide 16 mg/day, added to optimised RAS blockade, reduced proteinuria in patients with IgA nephropathy. This effect is indicative of a reduced risk of future progression to end-stage renal disease. TRF-budesonide could become the first specific treatment for IgA nephropathy targeting intestinal mucosal immunity upstream of disease manifestation.
Pharmalink AB.
IgA 肾病被认为与黏膜免疫系统功能障碍有关，其表现为肾脏 IgA 沉积，导致 20-40%的患者在 10-20 年内出现肾功能损害和终末期肾病。在这项试验（NEFIGAN）中，我们旨在评估一种新型布地奈德靶向释放制剂（TRF-布地奈德）的安全性和疗效，该制剂旨在将药物递送到 IgA 肾病患者的回肠远端。
我们进行了一项随机、双盲、安慰剂对照的 2b 期试验，包括 6 个月的导入期、9 个月的治疗期和 3 个月的随访期，在 10 个欧洲国家的 62 个肾病诊所进行。我们招募了年龄至少 18 岁的活检证实的原发性 IgA 肾病患者，这些患者尽管接受了最佳的肾素-血管紧张素系统（RAS）阻断治疗，但仍有持续性蛋白尿。我们使用计算机算法，以固定的 3 个块大小，将患者随机分配到 1:1:1 的比例，分别接受 16mg/天的 TRF-布地奈德、8mg/天的 TRF-布地奈德或安慰剂治疗，分层因素为基线尿蛋白肌酐比（UPCR）。患者在治疗期间每天早餐前 1 小时自行服用盲法胶囊。所有患者在整个试验中继续接受最佳的 RAS 阻断治疗。我们的主要结局是 9 个月治疗期间 UPCR 的平均变化，该变化在全分析集中进行评估，全分析集定义为所有接受至少一剂试验药物且至少有一次给药后疗效测量的随机患者。所有接受干预的患者均进行安全性评估。本试验在 ClinicalTrials.gov 注册，编号为 NCT01738035。
2012 年 12 月 11 日至 2015 年 6 月 25 日，150 名随机患者接受了治疗（安全性集），149 名患者符合全分析集的条件。总体而言，在 9 个月时，TRF-布地奈德（16mg/天加 8mg/天）与 UPCR 的平均下降 24.4%（SEM 7.7%）相关（与安慰剂相比，UPCR 的变化为 0.74；95%CI 0.59-0.94；p=0.0066）。在 9 个月时，接受 16mg/天治疗的 48 名患者的 UPCR 平均下降了 27.3%（0.71；0.53-0.94；p=0.0092），接受 8mg/天治疗的 51 名患者的 UPCR 平均下降了 21.5%（0.76；0.58-1.01；p=0.0290）；接受安慰剂的 50 名患者的 UPCR 平均增加了 2.7%。这种效果在整个随访期间持续存在。所有组的不良事件发生率相似（TRF-布地奈德 16mg/天组的 49 名患者中有 43 名[88%]，TRF-布地奈德 8mg/天组的 51 名患者中有 48 名[94%]，对照组的 50 名患者中有 42 名[84%]）。13 例严重不良事件中有 2 例可能与 TRF-布地奈德相关，分别为深静脉血栓形成（16mg/天组）和随访期间肾功能不明原因恶化（患者在 2 周内从 16mg/天逐渐减至 8mg/天，4 周后进行随访）。
TRF-布地奈德 16mg/天联合最佳 RAS 阻断治疗可降低 IgA 肾病患者的蛋白尿。这一效应表明未来发展为终末期肾病的风险降低。TRF-布地奈德可能成为针对 IgA 肾病肠道黏膜免疫的首个特异性治疗药物，该药物作用于疾病表现之前的靶点。
Pharmalink AB。
