Hansen-Pupp Ingrid, Hellström Ann, Hamdani Mohamed, Tocoian Adina, Kreher Nerissa C, Ley David, Hallberg Boubou
Lund University, Skåne University Hospital, Department of Clinical Sciences Lund, Pediatrics, Lasarettsgatan 40, SE-221 85 Lund, Sweden.
Institute of Neuroscience and Physiology, Sahlgrenska Academy at University of Gothenburg, Medicinaregatan 11-13, 40530 Gothenburg, Sweden.
Growth Horm IGF Res. 2017 Oct;36:44-51. doi: 10.1016/j.ghir.2017.08.004. Epub 2017 Aug 31.
To evaluate the feasibility of continuous longitudinal intravenous infusion of recombinant human insulin-like growth factor-1/recombinant human insulin-like growth factor binding protein-3 (rhIGF-1/rhIGFBP-3) for prevention of retinopathy of prematurity and other complications in extremely preterm infants (<28weeks' gestational age), based on initial sections of a phase II randomized controlled trial.
The phase II trial was designed in four sections (A-D); we report pharmacokinetic and adverse events (AEs) data pooled for Sections B and C. Infants in these study sections received rhIGF-1/rhIGFBP-3 or standard neonatal care up to postmenstrual age (weeks+days) 28+6 (Section B) or 29+6 (Section C). Dosing was variable/individualized and intended to establish serum IGF-1 within physiological intrauterine levels.
Nineteen infants were enrolled across Sections B/C: nine received rhIGF-1/rhIGFBP-3 and 10 standard neonatal care. Among the nine infants treated with study drug, mean (SD) dose was 95.1 (10.6)μg/kg/day and mean (SD) duration of infusion was 14.2 (6.1)days. Eight of nine (88.9%) treated infants had two or more dose changes during treatment. Mean serum IGF-1 levels during treatment were 23μg/L among treated infants compared with 14μg/L in control infants. Overall, 66.3% of IGF-1 measurements for treated infants were within target levels (20-60μg/L) versus 17.3% for control infants. Overall incidence of adverse events (AEs) was similar for treated versus control infants; AEs were generally as expected in this population, and no AEs were considered related to study treatment. There was no observed increase in infection rates (considered a possible risk with continuous intravenous infusion) between treated and control infants. Rates of hypoglycemia (considered a possible risk with IGF-1 treatment) were also similar between groups. There was one fatal serious AE of cardiac tamponade in the treated group (not considered treatment related).
Infusion of rhIGF-1/rhIGFBP-3 increased serum concentrations of IGF-1 and attainment of target levels relative to standard neonatal care. rhIGF-1/rhIGFBP-3 infusion was well tolerated with no safety signals. Although further work is required to optimize the dose regimen for attainment of physiological intrauterine levels, we believe the results reported support the feasibility of rhIGF-1/rhIGFBP-3 continuous longitudinal infusion in extremely preterm infants. The trial is registered at ClinicalTrials.gov (NCT01096784).
基于一项II期随机对照试验的初始部分，评估持续纵向静脉输注重组人胰岛素样生长因子-1/重组人胰岛素样生长因子结合蛋白-3（rhIGF-1/rhIGFBP-3）预防极早产儿（胎龄<28周）视网膜病变及其他并发症的可行性。
II期试验分为四个部分（A - D）；我们报告B和C部分汇总的药代动力学和不良事件（AE）数据。这些研究部分的婴儿接受rhIGF-1/rhIGFBP-3或标准新生儿护理，直至月经后年龄（周+天）达到28 + 6（B部分）或29 + 6（C部分）。给药是可变的/个体化的，旨在使血清IGF-1维持在生理宫内水平。
B/C部分共纳入19名婴儿：9名接受rhIGF-1/rhIGFBP-3治疗，10名接受标准新生儿护理。在接受研究药物治疗的9名婴儿中，平均（标准差）剂量为95.1（10.6）μg/kg/天，平均（标准差）输注持续时间为14.2（6.1）天。9名接受治疗的婴儿中有8名（88.9%）在治疗期间有两次或更多次剂量变化。治疗期间，治疗组婴儿的平均血清IGF-1水平为23μg/L，而对照组婴儿为14μg/L。总体而言，治疗组婴儿66.3%的IGF-1测量值在目标水平（20 - 60μg/L）内，而对照组为17.3%。治疗组与对照组婴儿的不良事件（AE）总发生率相似；AE在该人群中通常如预期，且无AE被认为与研究治疗相关。治疗组和对照组婴儿之间未观察到感染率增加（持续静脉输注可能存在的风险）。两组之间低血糖发生率（IGF-1治疗可能存在的风险）也相似。治疗组有1例致命严重AE为心包填塞（不认为与治疗相关）。
与标准新生儿护理相比，输注rhIGF-1/rhIGFBP-3可提高血清IGF-1浓度并达到目标水平。rhIGF-1/rhIGFBP-3输注耐受性良好，无安全信号。尽管需要进一步研究来优化剂量方案以达到生理宫内水平，但我们认为所报告的结果支持rhIGF-1/rhIGFBP-3在极早产儿中持续纵向输注的可行性。该试验已在ClinicalTrials.gov注册（NCT01096784）。
