Safety, pharmacokinetics, and exploratory efficacy of the oral ghrelin receptor agonist AC01 in heart failure with reduced ejection fraction (GOAL-HF1): a randomised, double-blind, placebo-controlled, phase 1b/2a study.

Existing inotropes are associated with adverse effects.

现有的正性肌力药物与不良反应相关。

In this exploratory study, we aimed to assess the safety and tolerability of AC01, a novel oral calcium-sensitising inotrope and ghrelin receptor agonist, in patients with HFrEF.

在这项探索性研究中，我们的目标是评估AC01的安全性和耐受性，这是一种新型口服钙敏化正性肌力药和ghrelin受体激动剂，用于治疗射血分数降低的心力衰竭(HFrEF)患者。

Methods

In this phase 1b/2a, randomised, double-blind, placebo-controlledstudy, adults aged 18-80 years with heart failure for at least 6 months and an ejection fraction of 40% or lower were enrolled at 14 sites in the Netherlands, the UK, Sweden, and Italy.

在这项1b/2a期、随机、双盲、安慰剂对照研究中，年龄在18-80岁之间，心力衰竭病史至少6个月且射血分数为40%或更低的成人在荷兰、英国、瑞典和意大利的14个研究地点被纳入研究。

All patients had a transvenous implantable cardioverter defibrillator for primary prevention, with back-up pacing to protect against excessive bradycardia.

所有患者植入了经静脉植入型心律转复除颤器以进行一级预防，并具有后备起搏功能以防止过度心动过缓。

Other eligibility criteria included sinus rhythm or permanent, persistent, or paroxysmal atrial fibrillation or flutter (only allowed in phase 2a), with a mean resting heart rate of 55-90 beats per min.

其他资格标准包括窦性心律或永久性、持续性或阵发性房颤或房扑（仅允许在第2a阶段），平均静息心率为每分钟55-90次。

Randomisation used permuted blocks, with block sizes of four for phase 1b and three for phase 2a.

随机分组使用了置换块，其中1b期的块大小为四，2a期的块大小为三。

In phase 1b, patients were enrolled in four sequential dose cohorts and randomly assigned 3:1 to ascending doses of AC01 (0·1 mg, 0·3 mg, 1·0 mg, or 3·0 mg) or placebo twice daily for 7 days.

在1b期，患者被纳入四个顺序剂量队列，并以3:1的比例随机分配到AC01（0·1 mg、0·3 mg、1·0 mg或3·0 mg）或安慰剂，每日两次，为期7天。

In phase 2a, patients were randomly assigned 1:1:1 to parallel groups receiving 1·0 mg AC01, 3·0 mg AC01 (1·0 mg AC01 on days 1 and 2 and 3·0 mg thereafter), or placebo orally twice daily for 28 days.

在2a期研究中，患者按1:1:1的比例随机分配到三个平行组，分别接受1·0 mg AC01、3·0 mg AC01（前两天每天1·0 mg，之后每天3·0 mg）或安慰剂，每日两次口服，为期28天。

Patients, study personnel, outcomes assessors, those analysing the data, and the sponsor were masked to treatment assignment.

患者、研究人员、结果评估者、数据分析人员以及赞助方均对治疗分配情况不知情。

The primary outcome was safety and tolerability.

主要结果是安全性和耐受性。

Safety was monitored by physical examination, vital signs, safety laboratory assessments, and 12-lead electrocardiograms (ECGs) periodically during the treatment period and until the end-of-study visit (day 12 in phase 1b and day 42 in phase 2a), and cardiac rhythm was continuously monitored remotely using a patch device until day 9 in phase 1b and until day 4 in phase 2a.

通过体检、生命体征、安全实验室评估和治疗期间及研究结束时（第1b阶段的第12天和第2a阶段的第42天）的12导联心电图（ECG）定期监测安全性，并使用贴片设备远程持续监测心律，直至第1b阶段的第9天和第2a阶段的第4天。

Adverse or unexpected events, signs, or symptoms were recorded.

记录了不良或意外事件、体征或症状。

This study is registered with ClinicalTrials.gov, NCT05642507, and has been completed.

该研究已在ClinicalTrials.gov注册，注册号为NCT05642507，并已完成。

Results

Between Feb 23, 2023, and Aug 28, 2025, 58 patients (53 [91%] male and five [9%] female patients with a median age of 66·0 years [IQR 60·3-72·0]) were randomly assigned: 32 in phase 1b and 26 in phase 2a.

在2023年2月23日至2025年8月28日期间，共有58名患者（53名[91%]男性和5名[9%]女性，中位年龄为66·0岁[四分位数间距60·3-72·0]）被随机分配：32名在1b期，26名在2a期。

In phase 1b, four cohorts of eight patients were enrolled; in each cohort, six patients were allocated to AC01 and two to placebo, with AC01 dose cohorts of 0·1 mg, 0·3 mg, 1·0 mg, and 3·0 mg.

在1b期，共有四组每组八名患者被纳入；在每组中，六名患者被分配到AC01组，两名患者被分配到安慰剂组，AC01剂量组分别为0·1 mg、0·3 mg、1·0 mg和3·0 mg。

In phase 2a, nine patients were allocated to 1·0 mg AC01, eight to 3·0 mg AC01, and nine to placebo.

在2a期试验中，九名患者被分配到1·0 mg AC01组，八名患者被分配到3·0 mg AC01组，另外九名患者被分配到安慰剂组。

There were 12 AC01-related adverse events in phase 1b and 18 in phase 2a.

在1b期有12起与AC01相关的不良事件，在2a期有18起。

There were no AC01-related serious adverse events; one treatment-related serious adverse eventof increased high-sensitivity cardiac troponin I concentration occurred in a patient receiving placebo in phase 1b.

没有与AC01相关的严重不良事件；在1b期接受安慰剂治疗的一名患者中，发生了与治疗相关的严重不良事件，即高敏肌钙蛋白I浓度增加。

Mild or moderate treatment-emergent adverse events were reported in 33 (80%) of 41 patients receiving AC01 and 12 (71%) of 17 patients receiving placebo.

在接受AC01治疗的41名患者中，有33名（80%）报告了轻度或中度的治疗后不良事件；在接受安慰剂治疗的17名患者中，有12名（71%）报告了轻度或中度的治疗后不良事件。

The most common treatment-emergent adverse events were hypotension, non-sustained ventricular tachycardia, dyspnoea, hyperglycaemia, dizziness or vertigo, and headache.

最常见的治疗后不良事件包括低血压、非持续性室性心动过速、呼吸困难、高血糖、头晕或眩晕以及头痛。

ECG data showed no apparent signs of tachycardia, new-onset tachyarrhythmias, myocardial ischaemia, or morphological or conduction abnormalities.

心电图数据显示没有明显的心动过速、新发的快速心律失常、心肌缺血或形态学或传导异常的迹象。

No case of symptomatic hypotension was reported, and there were no apparent effects of AC01 on high-sensitivity cardiac troponin I or NT-proBNP.

研究期间未报告任何症状性低血压病例，AC01对高敏心肌肌钙蛋白I或NT-proBNP没有明显影响。

There were no deaths during the study.

研究期间没有死亡病例。

interpretation

In patients with HFrEF, AC01 over 28 days appeared safe and well tolerated, and no major harms were identified in this early-phase study.

在患有射血分数降低的心力衰竭（HFrEF）患者中，AC01在28天的治疗期间显示出安全性和良好的耐受性，本早期研究未发现主要不良事件。

These findings support further investigations of AC01 in larger studies.

这些发现支持在更大规模的研究中进一步调查AC01。

funding

AnaCardio.

AnaCardio