A Study to Investigate the Efficacy, Safety, and Tolerability of DFV890 and MAS825 for Inflammatory Marker Reduction in Adult Participants With Coronary Heart Disease and Clonal Hematopoiesis of Indeterminate Potential (CHIP)

Study Overview
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Brief Summary
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This Phase 2a clinical trial will evaluate 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 (VAF ≥2%).

Detailed Description
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This is a multi-center, randomized, placebo-controlled, participant- and investigator-blinded study. The study consists 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 will be randomized to one of five treatment sequences. Based on the treatment sequence assignments, participants will start 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 will receive up-titrating doses of DFV890 or placebo at the corresponding study visits.

Official Title
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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)

Conditions
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Coronary Heart Disease, Clonal Hematopoiesis of Indeterminate Potential (CHIP)

Intervention / Treatment
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* Drug: MAS825
* Drug: MAS825 Placebo
* Drug: DFV890
* Drug: DFV890 placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: 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)]2. 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. Exclusion Criteria: 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 1. 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. Other protocol-defined inclusion/exclusion criteria may apply

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 80 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Treatment Sequence 1<br>Treatment Sequence 1 | Drug: MAS825<br>* Active MAS825 single dose<br>Drug: DFV890 placebo<br>* Oral tablet of DFV890 placebo once daily<br>|
| Experimental: Treatment Sequence 2<br>Treatment Sequence 2 | Drug: MAS825 Placebo<br>* MAS825 placebo single dose<br>Drug: DFV890<br>* Oral tablet of DFV890 active once daily<br>Drug: DFV890 placebo<br>* Oral tablet of DFV890 placebo once daily<br>|
| Experimental: Treatment Sequence 3<br>Treatment Sequence 3 | Drug: MAS825 Placebo<br>* MAS825 placebo single dose<br>Drug: DFV890<br>* Oral tablet of DFV890 active once daily<br>Drug: DFV890 placebo<br>* Oral tablet of DFV890 placebo once daily<br>|
| Experimental: Treatment Sequence 4<br>Treatment Sequence 4 | Drug: MAS825 Placebo<br>* MAS825 placebo single dose<br>Drug: DFV890<br>* Oral tablet of DFV890 active once daily<br>|
| Placebo Comparator: Treatment Sequence 5<br>Treatment Sequence 5 | Drug: MAS825 Placebo<br>* MAS825 placebo single dose<br>Drug: DFV890 placebo<br>* Oral tablet of DFV890 placebo once daily<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Serum levels of IL-6 and IL-18 | To evaluate the effect of various dose levels of DFV890 versus placebo to reduce circulating levels of inflammatory markers in participants with coronary heart disease and CHIP | From Day 22 to Day 92 (end of study) | 
| Serum level of IL-6 | To evaluate the effect of MAS825 versus placebo to reduce circulating levels of inflammatory markers in participants with coronary heart disease and CHIP. | Day 22 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Plasma trough concentrations (Ctrough) of DFV890 at steady-state | To assess the pharmacokinetics of DFV890 in participants with coronary heart disease and CHIP. | From Day 22 to Day 92 | 
| Serum concentrations of MAS825 after a single s.c. dose of MAS825 | To assess the pharmacokinetics of MAS825 in participants with coronary heart disease and CHIP. | From Day 1 to Day 85 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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coronary heart disease, CHIP, inflammatory marker reduction, NLRP3 inflammasome inhibitor