Cardiovascular Disease, Psoriasis
Conditions
Brief summary
Psoriasis, a common chronic inflammatory skin disease affecting approximately 2% of the population, is associated with increased cardiovascular (CV) risk. Despite the implication of inflammation in this excess risk, it remains unclear whether reducing inflammation reduces the risk of cardiac events. This study proposes to test whether Tildrakizumab, an FDA approved therapy for psoriasis that blocks IL-23 and the Th17 pathway of inflammation, improves coronary vascular function and coronary flow reserve, as measured by noninvasive imaging with cardiac positron emission tomography. In so doing, improvement in coronary vasoreactivity, endothelial function, and tissue perfusion may have beneficial effects on myocardial mechanics, left ventricular deformation and function and, ultimately, symptoms and prognosis. This research may offer novel insights into the contributors of CV risk in psoriasis and provide data to support the development of strategies to prevent cardiovascular events in psoriatic disease.
Detailed description
The primary objective of this study is to investigate the impact of Tildrakizumab therapy on coronary vasoreactivity and myocardial mechanics, as indicators of subclinical cardiovascular disease in patients with psoriatic disease and intermediate-high CV risk. Impaired coronary flow reserve (CFR) is a measure of coronary vasoreactivity and a manifestation of myocardial ischemia which may precede clinical CV events (and visible changes in plaque morphology) in high-risk patients with psoriatic disease. From previous studies, it is known that traditional risk factors underestimate cardiovascular risk in psoriatic disease. Tildrakizumab, a p19 inhibitor which blocks IL-23 and Th17 mediated inflammation, is an FDA approved therapy for moderate-severe psoriasis and has been shown to reduce inflammation. Furthermore, IL-17 is associated with endothelial dysfunction and atherosclerosis. The central hypothesis is that reducing systemic inflammation using tildrakizumab will quantitatively improve myocardial blood flow and CFR as measured by PET over 6 months; and this improvement in coronary vasoreactivity, endothelial function, and tissue perfusion may have beneficial effects on myocardial mechanics, left ventricular function and, ultimately, symptoms and prognosis. This is a single-arm open-label mechanistic clinical study in adult subjects with moderate-severe psoriasis and increased cardiovascular risk. We plan to enroll approximately 35 patients to receive Tildrakizumab over 6 months. The study will consist of 4-5 visits including a virtual or in person screening visit, a baseline visit in which baseline imaging tests will be conducted and study drug will be dispensed, two in person visits for which study drug will be given and monitoring of AE events and compliance, and a final visit in visit in which imaging tests will be repeated
Interventions
DRUGTildrakizumab
Tildrakizumab, a p19 inhibitor which blocks IL-23 and Th17 mediated inflammation, will be given for 6 months. As below, a baseline cardiac PET scan will be performed prior to initiation and after 6 months of treatment. Radiation: A cardiac PET scan will be performed at baseline and at 6 months
Sponsors
Marcelo F. Di Carli, MD, FACC
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 90 Years
Healthy volunteers
No
Inclusion criteria
In order for an individual to participate, they must meet all of the inclusion and
Exclusion criteria
as outlined below. Inclusion Criteria include the following: 1. Moderate-to-severe psoriasis 2. Ages 18-90 3. Body surface area (BSA) involvement ≥ 3% OR 5-point Physician Global Assessment (PGA) Score ≥ 3 OR Psoriasis Area and Severity Index (PASI) score ≥ 12 4. Patients who have failed biologic therapy, topical steroids, phototherapy, or other systemic therapies will be required to have a wash-out period, which will be calculated accordingly to the specific drug (Appendix 1) 5. Evidence of at least one cardiovascular risk factor which includes hsCRP ≥ 2 mg/L, DM, obesity (BMI\>25), hyperlipidemia, hypertension, family history of early coronary artery disease, or evidence of metabolic syndrome ---Metabolic syndrome defined as at least three of the following: glucose\>100mg/dl or taking hypoglycemic agent, HDL\<40mg/dl (men) or 50 mg/dl (women), triglycerides ≥150mg/dl, waist circumference \>40 in mean or \>35 in women, or blood pressure ≥130/85 or taking anti-hypertensive. 6. If the patient is on a statin therapy, they must be on a stable dose for at least 6 months prior to enrollment.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in Global Coronary Flow Reserve (CFR) After 6 Months of Therapy With Tildrakizumab | 24 weeks | Change (from baseline) in global CFR, as measured by PET imaging at 24 weeks after initiation of Tildrakizumab therapy. Coronary flow reserve (CFR), the ratio of peak vasodilator stress to rest myocardial blood flow (MBF), represents the maximal ability to augment coronary flow and myocardial perfusion. Absolute MBF was computed from the rest and stress myocardial perfusion PET images using commercially available software (Corridor4DM; Ann Arbor, Michigan) and a two-compartment tracer kinetic model. Impaired MBFR is defined as a ratio of \<2.0, which is associated with increased cardiovascular risk. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Correlation Between Change in Global CFR and Psoriasis Skin Severity | 24 weeks | Correlation between the change (from baseline) in global CFR and psoriasis skin severity scores (Body surface area \[BSA\], Physician's Global Assessment \[PGA\], Psoriasis Area and Severity Index \[PASI\]) at 24 weeks after initiation of Tildrakizumab |
| Change in Peak-stress Global Myocardial Blood Flow | 24 weeks | Change (from baseline) in peak-stress global myocardial blood flow (in mL/min/g) at 24 weeks after initiation of Tildrakizumab |
| Change in Peak-stress Global Coronary Vascular Resistance | 24 weeks | Change (from baseline) in peak-stress global coronary vascular resistance (in mm Hg/mL/min/g) at 24 weeks after initiation of Tildrakizumab |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Subjects Treated With Tildrakizumab Informed consent will be obtained from study participants willing to participate in MiNIMA. Study participants will then undergo the baseline rest/stress cardiac PET scan. The final PET scan will occur at 6 months after the intervention. | 31 |
| Total | 31 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Lost to Follow-up | 1 |
| Overall Study | Screen Fail | 5 |
Baseline characteristics
| Characteristic | Subjects Treated With Tildrakizumab |
|---|---|
| Age, Continuous | 61 years STANDARD_DEVIATION 11.3 |
| Atherosclerotic Coronary Artery Disease (ASCVD) Risk Score | 7 Percentage |
| CFR <2.5 | 15 Participants |
| Coronary Flow Reserve (CFR) | 2.63 Ratio STANDARD_DEVIATION 0.72 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 1 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 30 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Heart rate (HR) Peak HR | 95.2 bpm STANDARD_DEVIATION 27 |
| Heart rate (HR) Resting HR | 74 bpm STANDARD_DEVIATION 31 |
| High-Sensitivity C-Reactive Protein (hs-CRP) | 2.6 mg/L |
| High-sensitivity Troponin T (Hs-TnT) | 10 mg/L |
| Lipid panel HDL | 50 mg/dl |
| Lipid panel LDL | 103 mg/dl |
| Lipid panel Total cholesterol | 191 mg/dl |
| Lipid panel Triglycerides | 140 mg/dl |
| Myocardial Blood Flow (MBF) Global Rest MBF | 0.81 ml/min/g STANDARD_DEVIATION 0.15 |
| Myocardial Blood Flow (MBF) Global Stress MBF | 2.06 ml/min/g STANDARD_DEVIATION 0.42 |
| N-terminal Pro-Brain Natriuretic Peptide (NT-proBNP) | 57 pg/mL |
| Number of Participants with Coronary Artery Disease (CAD) | 5 Participants |
| Number of Participants with Diabetes mellitus | 5 Participants |
| Number of Participants with Dyslipidemia | 24 Participants |
| Number of Participants with Hypertension | 17 Participants |
| Number of Participants with Obesity | 18 Participants |
| Number of Participants with On Statin | 10 Participants |
| Number of Participants with Psoriatic Arthritis | 10 Participants |
| Physician's Global Assessment of Psoriasis (PGAP) | 3.0 scores on a scale |
| Psoriasis Area and Severity Index (PASI) | 10.9 scores on a scale |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 2 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants |
| Race (NIH/OMB) More than one race | 1 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 1 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 27 Participants |
| Sex: Female, Male Female | 12 Participants |
| Sex: Female, Male Male | 19 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 0 / 31 |
| other Total, other adverse events | 3 / 31 |
| serious Total, serious adverse events | 0 / 31 |
Outcome results
Primary
Change in Global Coronary Flow Reserve (CFR) After 6 Months of Therapy With Tildrakizumab
Change (from baseline) in global CFR, as measured by PET imaging at 24 weeks after initiation of Tildrakizumab therapy. Coronary flow reserve (CFR), the ratio of peak vasodilator stress to rest myocardial blood flow (MBF), represents the maximal ability to augment coronary flow and myocardial perfusion. Absolute MBF was computed from the rest and stress myocardial perfusion PET images using commercially available software (Corridor4DM; Ann Arbor, Michigan) and a two-compartment tracer kinetic model. Impaired MBFR is defined as a ratio of \<2.0, which is associated with increased cardiovascular risk.
Time frame: 24 weeks
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Subjects treated with Tildrakizumab | Change in Global Coronary Flow Reserve (CFR) After 6 Months of Therapy With Tildrakizumab | -0.03 CFR Ratio | Standard Deviation 0.83 |
Secondary
Change in Peak-stress Global Coronary Vascular Resistance
Change (from baseline) in peak-stress global coronary vascular resistance (in mm Hg/mL/min/g) at 24 weeks after initiation of Tildrakizumab
Time frame: 24 weeks
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Subjects treated with Tildrakizumab | Change in Peak-stress Global Coronary Vascular Resistance | -1.1 mm Hg/mL/min/g | Standard Deviation 13.15 |
Secondary
Change in Peak-stress Global Myocardial Blood Flow
Change (from baseline) in peak-stress global myocardial blood flow (in mL/min/g) at 24 weeks after initiation of Tildrakizumab
Time frame: 24 weeks
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Subjects treated with Tildrakizumab | Change in Peak-stress Global Myocardial Blood Flow | 0.07 ml/min/g | Standard Deviation 0.41 |
Secondary
Correlation Between Change in Global CFR and Psoriasis Skin Severity
Correlation between the change (from baseline) in global CFR and psoriasis skin severity scores (Body surface area \[BSA\], Physician's Global Assessment \[PGA\], Psoriasis Area and Severity Index \[PASI\]) at 24 weeks after initiation of Tildrakizumab
Time frame: 24 weeks
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Subjects treated with Tildrakizumab | Correlation Between Change in Global CFR and Psoriasis Skin Severity | 0.18 Spearman's rank correlation coefficient |
p-value: 0.35Spearman's Rank Correlation