Coronary Heart Disease
Conditions
Keywords
DFV890, Phase 2a, coronary heart disease, elevated hsCRP
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, to reduce key markers of inflammation related to CVD risk, such as IL-6 and IL-18, in approximately 24 people with known heart disease and an elevated marker of inflammation, hsCRP.
Detailed description
This was a multi-center, randomized, placebo-controlled, participant- and investigator-blinded study to evaluate the efficacy, safety, and tolerability of intra-individual dose escalation of DFV890 for inflammatory marker reduction in participants with coronary heart disease and elevated hsCRP. The study consisted of a screening period of up to 60 days, a treatment period of approximately 12 weeks, an end of treatment (EOT) visit on Day 85, which was one day after the last dose on Day 84, a follow-up period of approximately 1 week and a standard safety-follow-up call approximately 30 days following the last dose. Participants meeting all eligibility criteria were randomized in a 5:5:1:1 ratio to one of four treatment sequences (three DFV890 treatment sequences or a placebo-only sequence). The dose of DFV890 was uptitrated (according to the specific treatment sequence that the participant was assigned to) approximately every three weeks at the scheduled visits on Days 22, 43 and 64.
Interventions
DRUGDFV890
Oral film-coated tablets of DFV890 once daily
DRUGDFV890 Placebo
Oral film-coated tablets of DFV890 placebo once daily
Sponsors
Novartis Pharmaceuticals
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to 85 Years
Healthy volunteers
No
Inclusion criteria
* Male and female participants aged between 18 - 85 years (inclusive) at the start of screening will be included. * Subjects must have a body mass index (BMI) within the range of 18 - 45 kg/m2. 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. * Participants must have hsCRP levels ≥ 2 mg/L at two timepoints during screening. Screening values must be separated by a minimum of 8 days. The initial hsCRP value must be a minimum of 30 days after the qualifying MI or after any percutaneous coronary intervention (PCI) performed separately from the qualifying MI. * 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. * Patients with suspected or proven immunocompromised state at screening * History of ongoing, chronic, or major recurrent infectious disease, at the discretion of the investigator, at the start of 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 6 months prior to the start of screening. * Symptomatic Class IV heart failure (New York Heart Association) at the start of screening. * Planned coronary revascularization (PCI or CABG) or any other major surgical procedure during the study.
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 analysis was a model with 2 covariates (IL-18 baseline and bodyweight) and 1 random effect. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Trough Plasma Concentration (Ctrough) | 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. |
Countries
Canada, United States
Contacts
STUDY_DIRECTORNovartis Pharmaceuticals
Novartis Pharmaceuticals
Participant flow
Recruitment details
Participants were randomized in a 5:5:1:1 ratio to one of four treatment sequences
Pre-assignment details
The study consisted of a screening period of up to 60 days
Baseline characteristics
| Characteristic | — |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 12 Participants |
| Age, Categorical Between 18 and 65 years | 12 Participants |
| Age, Continuous | 64.1 years STANDARD_DEVIATION 8.61 |
| 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 / 12 | 0 / 21 | 0 / 10 | 0 / 20 | 0 / 28 | 0 / 22 | 0 / 1 | 0 / 1 | 0 / 20 | 0 / 2 |
| other Total, other adverse events | 2 / 12 | 2 / 21 | 2 / 10 | 0 / 20 | 4 / 28 | 4 / 22 | 1 / 1 | 1 / 1 | 0 / 20 | 0 / 2 |
| serious Total, serious adverse events | 0 / 12 | 0 / 21 | 2 / 10 | 0 / 20 | 0 / 28 | 0 / 22 | 0 / 1 | 0 / 1 | 0 / 20 | 0 / 2 |
Outcome results
None listed