A Phase 3b/4 Multi-center, Randomized, Open-label, Long-term Safety Study of Deucravacitinib in Comparison to Ustekinumab in Participants with Moderate-to-Severe Plaque Psoriasis (PRAGMATYK)

The primary objective of this study is to assess the cardiovascular safety of long-term use of deucravacitinib in comparison to ustekinumab in adults with moderate-to-severe plaque psoriasis. This objective addresses a critical clinical need to evaluate potential cardiovascular risks associated with prolonged systemic therapy in this patient population, which is known to have increased cardiovascular morbidity.

The secondary objective is to assess the overall safety profile of long-term use of deucravacitinib in comparison to ustekinumab in adults with moderate-to-severe plaque psoriasis. This evaluation provides comprehensive safety data beyond cardiovascular endpoints, encompassing the full spectrum of potential adverse events associated with extended treatment duration.

The clinical trial enrolled a total of **1,752 participants** diagnosed with **moderate to severe plaque psoriasis**. The study population consisted of **adult participants aged 40 years or older**, including both **male and female subjects**. Participants presented with moderate-to-severe disease severity, defined by a **Psoriasis Area and Severity Index (PASI)** score of 12 or greater, **Body Surface Area (BSA)** involvement of 10% or greater, and a **static Physician Global Assessment (sPGA)** score of 3 or higher at screening and baseline visits. All enrolled individuals were candidates for **phototherapy** or **systemic treatment** of psoriasis. A key characteristic of the study population was the presence of at least one **cardiovascular risk factor**, which included current cigarette smoking, **hypertension** or use of blood pressure-lowering medications, **dyslipidemia**, **diabetes mellitus type 1 or 2**, history of cardiovascular disease events such as **coronary revascularization procedures** including **percutaneous coronary intervention (PCI)** or **coronary artery bypass grafting (CABG)**, **myocardial infarction (MI)**, **cardiac arrest**, hospitalization for **unstable angina**, **acute coronary syndrome**, **stroke**, or **transient ischemic attack**, **obesity** defined by a **body mass index** of 30 kg/m² or greater, or family history of premature coronary heart disease. The trial did not include vulnerable populations.

This is a Phase 3b/4 multicenter, randomized, open-label, long-term safety study comparing **deucravacitinib** to **ustekinumab** in adult participants with **moderate-to-severe plaque psoriasis**. The trial is classified as a **low-intervention clinical trial** as both investigational medicinal products are already approved in EU Member States and will be used according to their local package inserts and regulations. The study employs a randomized design where participants are assigned to receive either deucravacitinib as the test product or ustekinumab as the **comparator**. Deucravacitinib is administered as a **film-coated tablet** via the **oral** route, while ustekinumab is administered as a **solution for injection in pre-filled syringe** via **subcutaneous injection**.

The primary objective of the trial is to assess the **cardiovascular safety** of long-term use of deucravacitinib in comparison to ustekinumab in adults with moderate-to-severe plaque psoriasis. The **primary endpoint** is defined as a composite cardiovascular endpoint consisting of adjudicated 3-point **MACE** (non-fatal **myocardial infarction**, non-fatal **stroke**, and cardiovascular death) plus **coronary revascularization**. Secondary endpoints include adjudicated events of non-fatal myocardial infarction, non-fatal stroke, cardiovascular death, coronary revascularization, 3-point MACE, **pulmonary embolism**, **deep vein thrombosis**, the composite of all **venous thromboembolic events** including pulmonary embolism, deep vein thrombosis and retinal vein occlusion, arterial thromboembolic events including retinal artery occlusion, **heart failure** requiring hospitalization or urgent care visit, **malignancy** excluding non-melanoma skin cancer, **non-melanoma skin cancer**, and **opportunistic infections** including **tuberculosis** and complicated **herpes zoster**. Additional secondary endpoints include **serious adverse events**, all-cause mortality, and adverse events leading to permanent treatment discontinuation, as well as laboratory tests comprising complete metabolic panel including liver function test and fasting lipid panel at baseline and every 26 weeks thereafter.

Eligible participants must be adults aged 40 years or older with moderate-to-severe plaque psoriasis defined by a **PASI** (Psoriasis Area and Severity Index) score of 12 or greater, **BSA** (Body Surface Area) involvement of 10% or greater, and **sPGA** (static Physician's Global Assessment) score of 3 or greater at both the screening visit and Day 1 visits. Participants must be candidates for **phototherapy** or systemic treatment of psoriasis. Additionally, eligible participants should have at least one of the following cardiovascular risk factors: current cigarette smoker, diagnosis of **hypertension** or use of blood pressure-lowering medications, diagnosis of **dyslipidemia**, **diabetes mellitus** type 1 or 2, history of one or more cardiovascular disease events including coronary revascularization procedures such as **PCI** (percutaneous coronary intervention) or **CABG** (coronary artery bypass grafting), myocardial infarction, cardiac arrest, hospitalization for unstable angina, **acute coronary syndrome**, stroke, or **transient ischemic attack**, obesity defined by a **body mass index** of 30 kg/m² or greater, or family history of premature coronary heart disease.

The maximum treatment period for all investigational products is 60 weeks. The maximum daily dose amount for deucravacitinib is 6 mg with a maximum total dose amount of 10,950 mg. For ustekinumab, the maximum daily dose amounts are 45 mg/ml and 90 mg/ml with maximum total dose amounts of 1,035 mg/ml and 2,070 mg/ml respectively. The estimated recruitment start date is December 15, 2025, and the estimated end date of the trial is January 16, 2031. Participant involvement spans the duration of the treatment period plus follow-up assessments. Study visits include a screening visit for eligibility assessment, Day 1 visit for randomization and treatment initiation, regular follow-up visits for safety and efficacy monitoring including laboratory assessments every 26 weeks, and an end-of-study visit. Conditions that may lead to early termination from the study include adverse events requiring permanent treatment discontinuation, occurrence of serious adverse events, participant withdrawal of consent, or investigator decision based on safety concerns.

The experimental treatment under investigation is deucravacitinib (sponsor product code BMS-986165), a chemical compound administered as a film-coated tablet via the oral route. The maximum daily dose is 6 milligrams, with a maximum total dose of 10,950 milligrams over the treatment period. The maximum treatment period is 60 months. This medicinal product is manufactured by Bristol-Myers Squibb International Corporation and will be used as the test intervention in this clinical trial.

The comparator treatment is ustekinumab, a protein-based biological agent formulated as a solution for injection in pre-filled syringe and administered via subcutaneous injection. Two dosing regimens are specified for ustekinumab in this study. The first regimen involves a maximum daily dose of 45 milligrams per milliliter, with a maximum total dose of 1,035 milligrams per milliliter over the treatment period. The second regimen involves a maximum daily dose of 90 milligrams per milliliter, with a maximum total dose of 2,070 milligrams per milliliter over the treatment period. Both ustekinumab regimens have a maximum treatment period of 60 months. The product will be over-labelled and repackaged for use in this trial.

The primary efficacy endpoint is a composite cardiovascular endpoint defined as adjudicated 3-point major adverse cardiovascular events (MACE), which includes non-fatal myocardial infarction, non-fatal stroke, and cardiovascular death, plus coronary revascularization. Secondary efficacy endpoints include adjudicated events of non-fatal myocardial infarction, non-fatal stroke, cardiovascular death, coronary revascularization, 3-point MACE (non-fatal myocardial infarction, non-fatal stroke, and cardiovascular death), pulmonary embolism, deep vein thrombosis, the composite of all venous thromboembolic events including pulmonary embolism, deep vein thrombosis and retinal vein occlusion, arterial thromboembolic events (including retinal artery occlusion), heart failure requiring hospitalization or urgent care visit, malignancy excluding non-melanoma skin cancer, non-melanoma skin cancer, and opportunistic infections including tuberculosis and complicated herpes zoster. Additional secondary endpoints include serious adverse events, all-cause mortality, and adverse events leading to permanent treatment discontinuation. Laboratory tests consisting of complete metabolic panel, including liver function test and fasting lipid panel, will be performed at baseline and every 26 weeks thereafter to assess efficacy and safety parameters.