Neonatal Intensive Care Unit, University College London, London, UK.
Department of Neonatology, Institute for Women's Health, University College London, London, UK.
BMJ Open. 2024 Aug 17;14(8):e086394. doi: 10.1136/bmjopen-2024-086394.
Chronic respiratory morbidity from bronchopulmonary dysplasia (BPD) remains the most common complication of preterm birth and has consequences for later respiratory, cardiovascular and neurodevelopmental outcomes. The early phases of respiratory illness are characterised by rapid consumption of endogenous surfactant and slow replenishment. Exogenous surfactant is routinely administered to infants born before 28 weeks of gestation as prophylaxis. Endogenous surfactant includes four proteins, known as surfactant proteins (SPs) A, B, C and D. Current bovine-derived and porcine-derived surfactant preparations only contain SPs B and C. SP-D has a key role in lung immune homeostasis as part of the innate immune system. Laboratory studies using recombinant SP-D have demonstrated reduced inflammation, which may be a pathway to reducing the associated morbidity from BPD. RESPONSE uses a recombinant fragment of human SP D (rfhSP-D), in a phase I safety and dose-escalation trial as the first stage in determining its effect in humans.
This is a single-centre, dose-escalation, phase I safety study aiming to recruit 24 infants born before 30 weeks gestation with respiratory distress syndrome. In addition to routine surfactant replacement therapy, participants will receive three doses of rfhSP-D via endotracheal route at either 1 mg/kg, 2 mg/kg or 4 mg/kg. The study uses a Bayesian continual reassessment method to make dose escalation decisions. Dose-limiting events (DLE) in this trial will be graded according to the published Neonatal Adverse Event Severity Score. The primary outcome of this study is to evaluate the safety profile of rfhSP-D across each dose level based on the profile of DLE to establish the recommended phase 2 dose (RP2D) of rfhSP-D.
The RESPONSE study has received ethical approval from London-Brent NHS Research Health Authority ethics committee. Results from the study will be published in peer-reviewed journals and presented at national and international conferences.
ISRCTN17083028, NCT05898633.
RESPONSE Protocol V.4.0 24th July 2024.
支气管肺发育不良（BPD）引起的慢性呼吸系统疾病仍然是早产儿最常见的并发症，对以后的呼吸、心血管和神经发育结果都有影响。呼吸疾病的早期阶段的特点是内源性表面活性剂的快速消耗和缓慢补充。外源性表面活性剂通常作为预防措施用于 28 周以下出生的婴儿。内源性表面活性剂包括四种蛋白质，称为表面活性剂蛋白（SP）A、B、C 和 D。目前的牛源性和猪源性表面活性剂制剂仅包含 SPB 和 C。SP-D 作为先天免疫系统的一部分，在肺免疫稳态中起着关键作用。使用重组 SP-D 的实验室研究表明炎症减少，这可能是降低 BPD 相关发病率的途径。RESPONSE 使用重组人 SP-D（rfhSP-D）的片段，在一项 I 期安全性和剂量递增试验中，作为确定其在人体中作用的第一阶段。
这是一项单中心、剂量递增的 I 期安全性研究，旨在招募 24 名患有呼吸窘迫综合征的 30 周以下出生的婴儿。除了常规的表面活性剂替代治疗外，参与者将通过气管内途径接受三次 rfhSP-D 剂量，剂量分别为 1mg/kg、2mg/kg 或 4mg/kg。该研究使用贝叶斯连续评估方法做出剂量递增决策。本试验中的剂量限制事件（DLE）将根据已发表的新生儿不良事件严重程度评分进行分级。该研究的主要结果是根据 DLE 特征评估每个剂量水平的 rfhSP-D 的安全性概况，以确定 rfhSP-D 的推荐 2 期剂量（RP2D）。
RESPONSE 研究已获得伦敦-布伦特国民保健署伦理委员会的伦理批准。该研究的结果将发表在同行评议的期刊上，并在国家和国际会议上发表。
ISRCTN80533355，NCT05898633。
RESPONSE 方案 V.4.0 2024 年 7 月 24 日。
