Steinmetz Jacob, Sørensen Anne Marie, Henriksen Hanne Hee, Lange Theis, Larsen Claus Falck, Johansson Pär I, Stensballe Jakob
Department of Anaesthesia and Trauma Centre, Centre for Head and Orthopaedics, Rigshospitalet, Copenhagen University Hospital, Blegdamsvej 9, 2100, Copenhagen, Denmark.
Section for Transfusion Medicine, Capital Region Blood Bank Rigshospitalet, Copenhagen University Hospital, Blegdamsvej 9, 2100, Copenhagen, Denmark.
Trials. 2016 Jul 19;17(1):327. doi: 10.1186/s13063-016-1439-5.
Haemorrhage remains a leading cause of morbidity and mortality in trauma patients. Fibrinogen is an essential endogenous component of haemostasis and the plasma level is associated with bleeding, transfusion and outcome. Fibrinogen concentrate is widely used to correct acquired hypofibrinogenaemia, recommended by several international guidelines for the treatment of trauma patients, but evidence is lacking regarding the treatment safety and efficacy. We aim to assess the efficacy and safety of an immediate pre-emptive first-line treatment with fibrinogen concentrate in patients with trauma haemorrhage in need of haemostatic resuscitation.
METHODS/DESIGN: This is a single-centre, randomized (1:1, active:placebo), placebo-controlled, double-blinded, investigator-initiated phase II trial. The trial population consists of 40 adult patients (>18 years) with traumatic, critical bleeding admitted to the Level 1 Trauma Centre at Rigshospitalet in Copenhagen, with immediate need for blood transfusion on arrival and an expected need for haemostatic resuscitation with multiple transfusions during the initial resuscitation. Patients will receive either pre-emptive administration of a bolus dose of 60-70 mg/kg fibrinogen concentrate (Riastap®) or placebo 0.9 % saline in equal volume to active treatment, both given as intravenous infusion blinded for the person administering the infusion. The primary end point is the change in thrombelastograph (TEG®) functional fibrinogen maximum amplitude in millimetres at 15 min after the intervention. The follow-up period on safety events and mortality will be until day 30. To detect a difference in the change from baseline to the 15-minute post-randomization measurement of 6-8 mm in TEG® functional fibrinogen maximum amplitude with a power of 0.90 and alpha of 0.05, we require 19 patients in each group. We have chosen to include 40 patients, 20 evaluable patients in each randomization group in case of attrition, in the present trial.
Patients considered to be included in the trial will temporarily have a compromised consciousness because of the acute, critical bleeding related to trauma, so scientific guardians will co-sign the informed consent form. Next of kin and the patients' general practitioner or the patients will co-sign as soon as possible. This trial will test whether immediate pre-emptive fibrinogen concentrate administered to adult trauma patients as first-line treatment of trauma haemorrhage will increase the clot strength as evaluated by thrombelastography, transfusion requirements and survival in patients receiving haemostatic resuscitation according to current standard of care.
EudraCT no. 2014-003978-16 (22/1 2015); ClinicalTrials.gov: NCT02344069 . Registered on 14 January 2015. Trial protocol version 4.2 (23-12-2014).
出血仍然是创伤患者发病和死亡的主要原因。纤维蛋白原是止血的重要内源性成分，血浆水平与出血、输血及预后相关。纤维蛋白原浓缩剂广泛用于纠正获得性低纤维蛋白原血症，被多项国际指南推荐用于治疗创伤患者，但关于其治疗安全性和有效性的证据不足。我们旨在评估对需要进行止血复苏的创伤出血患者立即进行抢先一线治疗使用纤维蛋白原浓缩剂的有效性和安全性。
方法/设计：这是一项单中心、随机（1:1，活性药物：安慰剂）、安慰剂对照、双盲、研究者发起的II期试验。试验人群包括40例成年患者（>18岁），因创伤性严重出血入住哥本哈根里格霍斯医院的1级创伤中心，入院时急需输血且预计在初始复苏期间需要多次输血进行止血复苏。患者将接受静脉输注60 - 70mg/kg纤维蛋白原浓缩剂（Riastap®）大剂量推注的抢先给药或与活性治疗等体积的安慰剂0.9%生理盐水，两种输注均对输液者进行盲法处理。主要终点是干预后15分钟血栓弹力图（TEG®）功能性纤维蛋白原最大振幅（以毫米为单位）的变化。安全事件和死亡率的随访期至第30天。为了在功效为0.90和α为0.05的情况下检测从基线到随机分组后15分钟测量时TEG®功能性纤维蛋白原最大振幅变化6 - 8毫米的差异，我们每组需要19例患者。在本试验中，我们选择纳入40例患者，每个随机分组中有20例可评估患者，以防出现损耗。
被认为纳入试验的患者由于与创伤相关的急性严重出血，意识会暂时受损，因此科学监护人将共同签署知情同意书。近亲以及患者的全科医生或患者将尽快共同签署。本试验将测试对成年创伤患者作为创伤出血的一线治疗立即给予抢先纤维蛋白原浓缩剂是否会增加根据当前护理标准接受止血复苏患者的凝血强度、输血需求和生存率。
欧洲药品管理局临床试验编号：2014 - 003978 - 16（2015年1月22日）；美国国立医学图书馆临床试验注册中心编号：NCT02344069。于2015年1月14日注册。试验方案版本4.2（2014年12月23日）。
