Clinical trial NCT04271540: MIcrovascular dysfuNction In Moderate-severe Psoriasis
Official title: Effects of Tildrakizumab on Coronary Microvascular Function in Moderate-Severe Psoriasis
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE4
Conditions: Psoriasis
Cardiovascular Disease
Lead sponsor: Brigham and Women's Hospital
Sponsor class: OTHER
First posted: 2020-02-17
Enrollment: 36
Sex: ALL
Minimum age (years): 18
Maximum age (years): 90
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

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

Eligibility 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.

Exclusion Criteria include the following:

1. Documented history of other systemic inflammatory diseases, including SLE and RA, which in the opinion of the investigator would be inappropriate for enrollment.
2. Prior history of untreated chronic infection (tuberculosis), severe fungal infection, or known HIV positive, chronic hepatitis B or C infection), prior history of active solid malignancy, myeloproliferative or lymphoproliferative disease within 5 years, excluding treated non-melanoma skin cancer
3. Renal insufficiency (CrCl \<40 ml/min)
4. NYHA class IV heart failure
5. Patients requiring chronic treatment with oral prednisone \>10mg/day, methotrexate, or other immunosuppressive agents.
6. Pregnancy and Breastfeeding

Primary outcomes:
measure: Change in global coronary flow reserve (CFR) after 6 months of therapy with Tildrakizumab
timeFrame: 24 weeks
Secondary outcomes:
measure: Correlation between change in global CFR and psoriasis skin severity
timeFrame: 24 weeks
measure: Change in peak-stress global myocardial blood flow
timeFrame: 24 weeks
measure: Change in peak-stress global coronary vascular resistance
timeFrame: 24 weeks
Other outcomes:
Locations:
city: Boston
country: United States
facility: Brigham and Women's Hospital
state: Massachusetts
Study officials:
affiliation: Brigham and Women's Hospital
name: Marcelo F Di Carli, MD
role: PRINCIPAL_INVESTIGATOR
References: