Clinical trial NCT06097663: 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)
Official title: 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)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Coronary Heart Disease
Clonal Hematopoiesis of Indeterminate Potential (CHIP)
Keywords: coronary heart disease
CHIP
inflammatory marker reduction
NLRP3 inflammasome inhibitor
Lead sponsor: Novartis
Sponsor class: INDUSTRY
First posted: 2023-10-24
Enrollment: 31
Sex: ALL
Minimum age (years): 18
Maximum age (years): 80
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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: 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.

Eligibility criteria: 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

Primary outcomes:
measure: Serum levels of IL-6 and IL-18
timeFrame: From Day 22 to Day 92 (end of study)
measure: Serum level of IL-6
timeFrame: Day 22
Secondary outcomes:
measure: Plasma trough concentrations (Ctrough) of DFV890 at steady-state
timeFrame: From Day 22 to Day 92
measure: Serum concentrations of MAS825 after a single s.c. dose of MAS825
timeFrame: From Day 1 to Day 85
Other outcomes:
Locations:
city: Saint Louis
country: United States
facility: Washington University
state: Missouri
city: Nashville
country: United States
facility: Vanderbilt University Medical Cent
state: Tennessee
city: Montreal
country: Canada
facility: Novartis Investigative Site
state: Quebec
city: Bonn
country: Germany
facility: Novartis Investigative Site
city: Frankfurt
country: Germany
facility: Novartis Investigative Site
city: Muenchen
country: Germany
facility: Novartis Investigative Site
Study officials:
affiliation: Novartis Pharmaceuticals
name: Novartis Pharmaceuticals
role: STUDY_DIRECTOR
References: