Coronary Heart Disease, Clonal Hematopoiesis of Indeterminate Potential (CHIP)
Conditions
Keywords
coronary heart disease, CHIP, inflammatory marker reduction, NLRP3 inflammasome inhibitor
Brief summary
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%).
Detailed description
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.
Interventions
DRUGMAS825
Active MAS825 single dose
DRUGMAS825 Placebo
MAS825 placebo single dose
DRUGDFV890
Oral tablet of DFV890 active once daily
DRUGDFV890 placebo
Oral tablet of DFV890 placebo once daily
Sponsors
Novartis Pharmaceuticals
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 80 Years
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Ratio to Baseline Serum Levels of IL-6 for DFV890 Based on an Emax Model | 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 | 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 | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| 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 | Ctrough is the observed plasma concentration that is just prior to the beginning of, or at the end of a dosing interval. |
| MAS825 Serum Concentrations | Day 22, Day 43, Day 64 and Day 85 | MAS825 serum concentrations were determined using a validated target-based sandwich ELISA. |
Countries
Canada, Germany, United States
Contacts
STUDY_DIRECTORNovartis Pharmaceuticals
Novartis Pharmaceuticals
Participant flow
Recruitment details
Participants were randomized in a 4:4:4:1:1 ratio to one of the five treatment sequences.
Pre-assignment details
The study consisted of a screening period up to 30 days.
Baseline characteristics
| Characteristic | — |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 23 Participants |
| Age, Categorical Between 18 and 65 years | 8 Participants |
| Age, Continuous | 69.8 years STANDARD_DEVIATION 6.4 |
| Race/Ethnicity, Customized Black or African American | 0 Participants |
| Race/Ethnicity, Customized White | 2 Participants |
| Sex: Female, Male Female | 2 Participants |
| Sex: Female, Male Male | 10 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk | EG006 affected / at risk | EG007 affected / at risk | EG008 affected / at risk | EG009 affected / at risk |
|---|---|---|---|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 10 | 0 / 16 | 0 / 9 | 0 / 16 | 0 / 11 | 0 / 22 | 0 / 18 | 0 / 16 | 0 / 11 | 0 / 2 |
| other Total, other adverse events | 1 / 10 | 6 / 16 | 2 / 9 | 3 / 16 | 7 / 11 | 9 / 22 | 8 / 18 | 3 / 16 | 1 / 11 | 0 / 2 |
| serious Total, serious adverse events | 0 / 10 | 0 / 16 | 0 / 9 | 0 / 16 | 0 / 11 | 0 / 22 | 0 / 18 | 0 / 16 | 0 / 11 | 0 / 2 |
Outcome results
None listed