A Randomized, Placebo-controlled, Parallel-group, Investigator- and Participant-blinded Phase 2a Study to Investigate the Efficacy, Safety, and Tolerability of DFV890 and MAS825 for Inflammatory Marker Reduction in an Adult Population With Coronary Heart Disease and Clonal Hematopoiesis of Indeterminate Potential (CHIP)
试验速览
- 阶段
- 2 期
- 状态
- 已完成
- 入组人数
- 31
- 试验地点
- 6
- 主要终点
- Ratio to Baseline Serum Levels of IL-6 for DFV890 Based on an Emax Model
研究概览
简要总结
This Phase 2a clinical trial evaluated the effectiveness, safety, and tolerability of increasing dose strengths of an oral daily medication, DFV890, administered for 12 weeks, or a single s.c. dose of MAS825, to reduce key markers of inflammation related to CVD risk, such as IL-6 and IL-18, in approximately 28 people with known coronary heart disease and TET2 or DNMT3A CHIP (variant allele frequency [VAF] ≥2%).
详细描述
This was a multi-center, randomized, placebo-controlled, participant- and investigator-blinded study.
The study consisted of a screening period up to 30 days; a treatment period of approximately 12 weeks with an end of treatment (EOT) visit on Day 85, which is one day after the last dose of DFV890 or placebo; a follow-up period of approximately 1 week; and a standard safety follow-up call approximately 30 days following the last dose. The overall study duration is approximately 21 weeks.
Participants were randomized to one of five treatment sequences. Based on the treatment sequence assignments, participants started on either a combination of MAS825 and placebo, DFV890 and placebo, or placebo and placebo on Day 1, and then, within each DFV890 treatment sequence, participants received up-titrating doses of DFV890 or placebo at the corresponding study visits. None of the treatment sequences included a combination of both active DFV890 and active MAS825.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
入排标准
- 年龄范围
- 18 Years 至 80 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Male and female participants aged between 18 - 80 years (inclusive) at the start of screening will be included.
- •Participants must have a body mass index (BMI) within the range of 18 - 40 kg/m2 at screening. BMI = Body weight (kg) / [Height (m)]
- •Documented spontaneous myocardial infarction (MI) (diagnosed according to the universal MI criteria with or without evidence of ST segment elevation) at least 30 days before the start of screening (Thygesen et al 2007).
- •Known presence of CHIP, restricted to driver mutations in TET2 or DNMT3A with a VAF ≥2%, as documented in the participant's medical history.
- •For participants on statin therapy (HMG-CoA reductase inhibitor) as clinically indicated, participants must be on a stable regimen (at least 4 weeks before randomization), with no planned statin dose changes over the course of the trial treatment period. Unplanned statin dose changes during the trial treatment period may occur.
排除标准
- •Patients receiving concomitant medications that are known to be strong or moderate inducers of cytochrome CYP2C9 enzyme and/or strong inducers of CYP3A, strong inhibitors of CYP2C9 and/or strong or moderate inhibitors of CYP3A and the treatment cannot be discontinued or switched to a different medication within 5 half-lives or 1 week (whichever is longer) prior to Day 1 and for the duration of the study.
- •At screening, pre-malignant clonal cytopenias or clonal cytopenia of unknown significance (CCUS).
- •History of ongoing, chronic, or major recurrent infectious disease, at the discretion of the Investigator, at the start of screening.
- •Patients with suspected or proven immunocompromised state at screening.
- •Use of any biologic drugs targeting the immune system within 26 weeks of Day
- •Multi-vessel coronary artery bypass graft (CABG) surgery within the past 3 years prior to the start of screening.
- •Planned coronary revascularization (percutaneous coronary intervention (PCI) or CABG) or any other major surgical procedure during the study (until End of Study (EOS)).
- •Symptomatic Class IV heart failure (New York Heart Association [NYHA]) at the start of screening.
研究组 & 干预措施
Treatment Sequence 2
On Day 1, participants received the single s.c. dose of MAS825 placebo and DFV890 oral placebo QD. Participants continued receiving DFV890 oral placebo QD until Day 22 when participants started receiving DFV890 10mg QD. The dose of DFV890 was uptitrated to 25mg on Day 43 and to 100mg on Day 64.
干预措施: DFV890 (Drug)
Treatment Sequence 3
On Day 1, participants received the single s.c. dose of MAS825 placebo and DFV890 oral placebo QD. Participants continued receiving DFV890 oral placebo QD until Day 22 when participants started receiving DFV890 25mg QD. The dose of DFV890 was uptitrated to 50mg on Day 43 and to 100mg on Day 64.
干预措施: DFV890 (Drug)
Treatment Sequence 4
On Day 1, participants received the single s.c. dose of MAS825 placebo and DFV890 10 mg QD. Participants continued receiving DFV890 10 mg QD until Day 22 when the dose of DFV890 was uptitrated to 25mg QD. On Day 43 the dose of DFV890 was uptitrated to 50mg and on Day 64 to 100mg.
干预措施: DFV890 (Drug)
Treatment Sequence 3
On Day 1, participants received the single s.c. dose of MAS825 placebo and DFV890 oral placebo QD. Participants continued receiving DFV890 oral placebo QD until Day 22 when participants started receiving DFV890 25mg QD. The dose of DFV890 was uptitrated to 50mg on Day 43 and to 100mg on Day 64.
干预措施: DFV890 placebo (Drug)
Treatment Sequence 5
On Day 1, participants received the single s.c. dose of MAS825 placebo and DFV890 oral placebo QD. Participants continued receiving DFV890 oral placebo QD until Day 84.
干预措施: DFV890 placebo (Drug)
Treatment Sequence 1
On Day 1, participants received the single s.c. dose of MAS825 and DFV890 oral placebo QD. Participants continued receiving DFV890 oral placebo QD until Day 84.
干预措施: DFV890 placebo (Drug)
Treatment Sequence 2
On Day 1, participants received the single s.c. dose of MAS825 placebo and DFV890 oral placebo QD. Participants continued receiving DFV890 oral placebo QD until Day 22 when participants started receiving DFV890 10mg QD. The dose of DFV890 was uptitrated to 25mg on Day 43 and to 100mg on Day 64.
干预措施: DFV890 placebo (Drug)
Treatment Sequence 5
On Day 1, participants received the single s.c. dose of MAS825 placebo and DFV890 oral placebo QD. Participants continued receiving DFV890 oral placebo QD until Day 84.
干预措施: MAS825 Placebo (Drug)
Treatment Sequence 2
On Day 1, participants received the single s.c. dose of MAS825 placebo and DFV890 oral placebo QD. Participants continued receiving DFV890 oral placebo QD until Day 22 when participants started receiving DFV890 10mg QD. The dose of DFV890 was uptitrated to 25mg on Day 43 and to 100mg on Day 64.
干预措施: MAS825 Placebo (Drug)
Treatment Sequence 3
On Day 1, participants received the single s.c. dose of MAS825 placebo and DFV890 oral placebo QD. Participants continued receiving DFV890 oral placebo QD until Day 22 when participants started receiving DFV890 25mg QD. The dose of DFV890 was uptitrated to 50mg on Day 43 and to 100mg on Day 64.
干预措施: MAS825 Placebo (Drug)
Treatment Sequence 4
On Day 1, participants received the single s.c. dose of MAS825 placebo and DFV890 10 mg QD. Participants continued receiving DFV890 10 mg QD until Day 22 when the dose of DFV890 was uptitrated to 25mg QD. On Day 43 the dose of DFV890 was uptitrated to 50mg and on Day 64 to 100mg.
干预措施: MAS825 Placebo (Drug)
Treatment Sequence 1
On Day 1, participants received the single s.c. dose of MAS825 and DFV890 oral placebo QD. Participants continued receiving DFV890 oral placebo QD until Day 84.
干预措施: MAS825 (Drug)
结局指标
主要结局
Ratio to Baseline Serum Levels of IL-6 for DFV890 Based on an Emax Model
时间窗: Baseline (before first dose of study drug), 3 weeks after the start of a dosing period for DFV890 (between Day 22 and Day 85, depending on treatment sequence assignment)
Serum levels of IL-6 at 3 weeks after the start of a dosing period for DFV890. The circulating serum levels of the cytokine IL-6 were measured by a validated enzyme-linked immunosorbent assay (ELISA) assay at a qualified vendor. The Emax model selected for IL-6 analysis was a model with 2 covariates (IL-6 baseline and bodyweight) and 1 random effect.
Ratio to Baseline Serum Levels of IL-18 for DFV890 Based on an Emax Model
时间窗: Baseline (before first dose of study drug), 3 weeks after the start of a dosing period for DFV890 (between Day 22 and Day 85, depending on treatment sequence assignment)
Serum levels of IL-18 at 3 weeks after the start of a dosing period for DFV890. The circulating serum levels of the cytokine IL-18 were measured by a validated enzyme-linked immunosorbent assay (ELISA) assay at a qualified vendor. The Emax model selected for IL-18 was a model with one covariate (IL-18 baseline) and 1 random effect.
Ratio to Baseline Serum Levels of IL-6 for MAS825 Based on a Traditional Linear Regression Model
时间窗: Baseline (before first dose of study drug), 3 weeks after a single MAS825 dose on Day 1.
Serum level of IL-6 at Week 3 for MAS825. The circulating serum levels of the cytokine IL-6 was measured by a validated enzyme-linked immunosorbent assay (ELISA) assay at a qualified vendor. Data was analyzed with a a traditional linear regression model including treatment as a fixed categorical effect, a random intercept effect for participant, and the baseline value of the biomarker and baseline body weight as covariates.
次要结局
- Trough Plasma Concentration (Ctrough) of DFV890 at Steady-state(After the last dose of each 3-week dosing period: Day 22 pre-dose, Day 43 pre-dose, Day 64 pre-dose, or Day 85, depending on treatment sequence assignment)
- MAS825 Serum Concentrations(Day 22, Day 43, Day 64 and Day 85)