Efficacy and safety of relacorilant for the treatment of patients with Cushing's syndrome (GRACE): a multicentre, phase 3, double-blind, placebo-controlled, randomised-withdrawal study.

The aim of this study was to assess the efficacy and safety of relacorilant in adults with endogenous hypercortisolism.

本研究的目的是评估 Relacorilant 在成年内源性高皮质醇血症患者中的疗效和安全性。

Methods

This multicentre, phase 3, double-blind, placebo-controlled, randomised-withdrawal study enrolled adults with endogenous hypercortisolism and hypertension, hyperglycaemia, or both and was conducted at 77 study centres across 11 countries.

这项多中心、III期、双盲、安慰剂对照、随机停药研究招募了患有内源性高皮质醇血症和高血压、高血糖或两者兼有的成年人，研究在11个国家的77个研究中心进行。

Key inclusion criteria included being aged 18-80 years with at least two clinical signs or symptoms of hypercortisolism.

关键的纳入标准包括年龄在18-80岁之间，并且至少有两项高皮质醇血症的临床症状或体征。

In the open-label phase, patients received oral, once-daily relacorilant (escalation from 100 mg up to 400 mg) for 22 weeks.

在开放标签阶段，患者每天一次口服100 mg至400 mg的relacorilant，持续22周。

Patients who met response criteria were randomly assigned (1:1) by the interactive web response system to continue relacorilant 400 mg (or highest tolerated dose) or placebo for 12 weeks in the randomised-withdrawal phase.

符合反应标准的患者通过互动网络响应系统以1:1的比例随机分配，继续服用400 mg的relacorilant（或最高耐受剂量）或安慰剂，持续12周的随机撤药阶段。

Participants and investigators were masked to treatment assignment.

参与者和研究人员对治疗分配情况进行了盲法处理。

The primary outcome was the proportion of patients who lost hypertension response during the randomised-withdrawal phase compared between relacorilant and placebo at week 12.

主要结果是随机撤药阶段患者失去高血压反应的比例，在第12周时比较relacorilant和安慰剂之间的差异。

As per protocol, this outcome was assessed in all participants who received at least one dose of study drug in the study period (intention-to-treatpopulation).

根据方案，在研究期间至少接受过一次研究药物的参与者中评估了这一结果（意向治疗人群）。

Missing randomised-withdrawal week 12 values were considered a loss of response.

缺失的随机撤药第12周值被视为反应丧失。

Safety was assessed in all enrolled patients who received at least one dose of study drug in that period.

在该期间接受至少一次研究药物剂量的所有入组患者均进行了安全性评估。

This study is registered with ClinicalTrials.gov, NCT03697109.

该研究已在ClinicalTrials.gov注册，注册号为NCT03697109。

Results

Between Oct 16, 2018, and April 15, 2024, 404 patients were screened, 152 were enrolled, and 95 completed the open-label relacorilant phase. 62 patients met response criteria and were randomly assigned to relacorilant (30 total participants [21 met hypertension response criteria]) or placebo (32 total participants [22 met hypertension response criteria]).

在2018年10月16日至2024年4月15日期间，共筛查了404名患者，152名被纳入研究，95名完成了开放标签的relacorilant阶段。62名患者符合反应标准，并被随机分配到relacorilant组（共30名参与者[21名达到高血压反应标准]）或安慰剂组（共32名参与者[22名达到高血压反应标准]）。

In the 30 participants in the relacorilant group, the mean age was 46·6 years (SD 11·0), 22 (73%) were female, and eight (27%) were male.

在relacorilant组的30名参与者中，平均年龄为46.6岁（标准差11.0），22名（73%）为女性，8名（27%）为男性。

In the 32 participants in the placebo group, the mean age was 48·8 years (SD 14·4), 26 (81%) were female, and six (19%) were male.

在安慰剂组的32名参与者中，平均年龄为48.8岁（标准差14.4），26人（81%）为女性，6人（19%）为男性。

During the randomised-withdrawal phase, significantly more patients with baseline hypertension who were randomly assigned to placebo lost hypertension control compared with those who continued relacorilant (proportion difference 34%; odds ratio 0·17 [95% CI 0·04-0·77]; p=0·022).

在随机撤药阶段，与继续使用relacorilant的患者相比，被随机分配到安慰剂的基线高血压患者失去高血压控制的比例显著更高（比例差异34%；优势比0.17 [95% 置信区间0.04-0.77]；p=0.022）。

In the randomised-withdrawal phase safety population, the most common adverse events in the 30 participants given relacorilant and the 32 participants given placebo were back pain (5 [17%] vs 6 [19%]), acne (3 [10%] vs 0), arthralgia (3 [10%] vs 3 [9%]), bursitis (3 [10%] vs 0), headache (3 [10%] vs 4 [13%]), and insomnia (0 vs 4 [13%]).

在随机停药阶段的安全人群中，给予30名受试者relacorilant和32名受试者安慰剂的最常见不良事件是背痛（5 [17%] vs 6 [19%]）、痤疮（3 [10%] vs 0）、关节痛（3 [10%] vs 3 [9%]）、滑囊炎（3 [10%] vs 0）、头痛（3 [10%] vs 4 [13%]）和失眠（0 vs 4 [13%]）。

There were no cases of excessive glucocorticoid receptor antagonism, adrenal insufficiency, vaginal bleeding associated with endometrial hypertrophy, drug-induced hypokalaemia, or drug-induced QT interval prolongation.

没有出现过度的糖皮质激素受体拮抗、肾上腺功能不全、与子宫内膜增生相关的阴道出血、药物引起的低钾血症或药物引起的QT间期延长的病例。

interpretation

Patients treated with relacorilant were more likely to maintain hypertension control compared with patients treated with placebo.

接受relacorilant治疗的患者比接受安慰剂治疗的患者更有可能维持高血压控制。

The findings support consideration of relacorilant as a therapeutic option to reduce the harmful and debilitating effects of endogenous hypercortisolism.

这些发现支持将relacorilant作为减少内源性高皮质醇血症有害和致残效应的治疗选择进行考虑。

funding

Corcept Therapeutics.

科瑞普治疗学公司