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%).
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.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
QUADRUPLE
Enrollment
31
Active MAS825 single dose
MAS825 placebo single dose
Oral tablet of DFV890 active once daily
Oral tablet of DFV890 placebo once daily
Washington University
St Louis, Missouri, United States
Vanderbilt University Medical Cent
Nashville, Tennessee, United States
Novartis Investigative Site
Montreal, Quebec, Canada
Novartis Investigative Site
Frankfurt am Main, Hesse, Germany
Novartis Investigative Site
Bonn, Germany
Novartis Investigative Site
München, Germany
Ratio to Baseline Serum Levels of IL-6 for DFV890 Based on an Emax Model
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.
Time frame: 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)
Ratio to Baseline Serum Levels of IL-18 for DFV890 Based on an Emax Model
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.
Time frame: 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)
Ratio to Baseline Serum Levels of IL-6 for MAS825 Based on a Traditional Linear Regression Model
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.
Time frame: Baseline (before first dose of study drug), 3 weeks after a single MAS825 dose on Day 1.
Trough Plasma Concentration (Ctrough) of DFV890 at Steady-state
Ctrough is the observed plasma concentration that is just prior to the beginning of, or at the end of a dosing interval.
Time frame: 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
MAS825 serum concentrations were determined using a validated target-based sandwich ELISA.
Time frame: Day 22, Day 43, Day 64 and Day 85
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