Evaluation of Tapering Systemic Immunosuppressive Therapy on Maintaining Minimal Disease Activity in Psoriatic Arthritis Using Methotrexate Disodium and Drug Combination

The primary objective of this clinical trial is to evaluate the impact of tapering systemic **immunosuppressive** therapy in a treat-to-target approach on maintaining minimal disease activity (MDA) in adult subjects with **psoriatic arthritis** (PsA) who have achieved stable MDA. This is clinically relevant as it aims to determine the feasibility of reducing medication burden while maintaining disease control, potentially minimizing long-term side effects associated with continuous high-dose immunosuppressive therapy.

Secondary objectives include:

• Investigating the effects of tapering systemic immunosuppressive therapy on multidimensional aspects of PsA disease activity.
• Assessing the effects of tapering systemic immunosuppressive therapy on subject safety.

The clinical trial involves adult participants diagnosed with **psoriatic arthritis** (PsA) who are in a state of stable minimal disease activity (MDA). The study population includes both male and female subjects aged 18 years and older. Participants have been selected based on their diagnosis according to the CASPAR criteria and their ability to maintain MDA for at least six months. The trial does not specify the total number of participants, as this information was not provided by the sponsor. Participants have been on a stable treatment regimen without alterations for at least six months, involving conventional synthetic disease-modifying antirheumatic drugs (csDMARDs), biologic DMARDs (bDMARDs), targeted synthetic DMARDs (tsDMARDs), or glucocorticoids. The trial includes a vulnerable population, indicating that special considerations may be necessary for their participation. Lifestyle factors such as diet and physical activity are not specified in the available data.

The clinical trial is designed as a **randomized**, controlled, open-label, assessor-blinded, parallel-group Phase III study. The primary objective is to evaluate the impact of tapering systemic immunosuppressive therapy in a treat-to-target approach on maintaining minimal disease activity (MDA) in adult subjects with **psoriatic arthritis**. The trial is expected to run from September 15, 2020, to December 31, 2026, with a total duration of 24 months for each participant. Participants will be randomly assigned to treatment groups and will undergo a series of study visits to monitor their condition and response to treatment.

The sequence of study visits includes an initial screening visit to confirm eligibility based on criteria such as age, diagnosis according to CASPAR criteria, and stable MDA status for at least six months. Following the screening, participants will attend baseline visits to establish their current health status and treatment regimen. Subsequent follow-up visits will occur at regular intervals to assess the primary endpoint, which is the presence of MDA 12 months after baseline, and secondary endpoints such as PASDAS, DAPSA, and mCPDAI scores, among others. The end-of-study visit will conclude the participant's involvement, evaluating the long-term effects of the treatment tapering strategy.

Participants are expected to be involved in the trial for a maximum of 24 months, with conditions for early termination including significant adverse events or loss of MDA that cannot be managed within the study protocol. The trial will utilize a variety of systemic immunosuppressive therapies, including **methotrexate disodium**, **abatacept**, and **certolizumab pegol**, among others, administered through various routes such as subcutaneous and oral. The study aims to provide valuable insights into the management of psoriatic arthritis by exploring the potential for reducing medication without compromising disease control.

The clinical trial involves the administration of several experimental and non-experimental treatments to evaluate their impact on maintaining minimal disease activity in adult subjects with **psoriatic arthritis**. The experimental medication **Methotrexate Disodium** is provided in two pharmaceutical forms: a solution for injection and a tablet. The solution for injection is administered subcutaneously with a maximum daily dose of 25 mg and a total dose of 2600 mg over a 24-week period. The tablet form is administered orally with a maximum daily dose of 30 mg and a total dose of 3120 mg over the same period.

**Abatacept** is another experimental treatment used in the trial, available in multiple forms. The solution for injection in a pre-filled syringe and pen is administered subcutaneously with a maximum daily dose of 125 mg and a total dose of 1300 mg over 24 weeks. Additionally, a powder for concentrate for solution for infusion is administered intravenously with a maximum daily dose of 1000 mg and a total dose of 26000 mg over the trial period.

**Certolizumab Pegol** is administered as a solution for injection in both a dose-dispenser cartridge and a pre-filled syringe or pen. The administration route is subcutaneous, with a maximum daily dose of 400 mg and a total dose of 10400 mg over 24 weeks.

**Secukinumab** is provided as a solution for injection in a pre-filled pen and syringe, administered subcutaneously. The maximum daily dose is 300 mg, with a total dose of 7800 mg over the trial duration.

**Risankizumab** is administered as a solution for injection in a pre-filled syringe, subcutaneously, with a maximum daily dose of 150 mg and a total dose of 1300 mg over 24 weeks.

**Etanercept** is administered as a solution for injection subcutaneously, with a maximum daily dose of 50 mg and a total dose of 5.2 g over the trial period.

**Sulfasalazine** is provided as a film-coated tablet, administered orally, with a maximum daily dose of 2000 mg and a total dose of 1460 g over 24 weeks.

**Tofacitinib** is available in two forms: prolonged-release tablets and film-coated tablets. The prolonged-release tablets are administered orally with a maximum daily dose of 11 mg and a total dose of 8030 mg, while the film-coated tablets have a maximum daily dose of 10 mg and a total dose of 7300 mg over the trial period.

**Infliximab** is administered as a powder for concentrate for solution for infusion intravenously, with a maximum daily dose of 5 mg/kg and a total dose of 65 mg/kg over 24 weeks.

**Upadacitinib** is provided as prolonged-release tablets, administered orally, with a maximum daily dose of 15 mg and a total dose of 10950 mg over the trial period.

**Leflunomide** is administered as a coated tablet orally, with a maximum daily dose of 20 mg and a total dose of 14.6 g over 24 weeks.

**Apremilast** is provided as film-coated tablets, administered orally, with a maximum daily dose of 60 mg and a total dose of 43.8 g over the trial period.

**Adalimumab** is administered as a solution for injection subcutaneously, with a maximum daily dose of 40 mg and a total dose of 2080 mg over 24 weeks.

**Guselkumab** is provided as a solution for injection in a pre-filled pen, administered subcutaneously, with a maximum daily dose of 100 mg and a total dose of 1300 mg over the trial period.

**Ustekinumab** is administered as a solution for injection subcutaneously, with a maximum daily dose of 90 mg and a total dose of 780 mg over 24 weeks.

**Prednisolone** is provided as a tablet, administered orally, with a maximum daily dose of 50 mg and a total dose of 36.5 g over the trial period.

**Ixekizumab** is administered as a solution for injection in a pre-filled pen subcutaneously, with a maximum daily dose of 80 mg and a total dose of 2080 mg over 24 weeks.

**Golimumab** is provided as a solution for injection in a pre-filled syringe, administered subcutaneously, with a maximum daily dose of 50 mg and a total dose of 1300 mg over the trial period.

Participant compliance with the dosing schedules is monitored throughout the trial to ensure adherence to the treatment protocols. The trial aims to assess the efficacy of these treatments in maintaining minimal disease activity in subjects with psoriatic arthritis.

The efficacy of the clinical trial will be assessed through a series of primary and secondary endpoints designed to evaluate the impact of tapering systemic immunosuppressive therapy on maintaining minimal disease activity (MDA) in adult subjects with psoriatic arthritis. The primary endpoints include the presence of MDA 12 months after baseline and the mean Psoriatic Arthritis Disease Activity Score (PASDAS) at month 12. Secondary endpoints encompass a range of measures, including PASDAS, Disease Activity in Psoriatic Arthritis (DAPSA), and modified Composite Psoriatic Disease Activity Index (mCPDAI). Additional assessments will include the number of swollen and tender joints, tender entheseal points using SPARCC, LEI, and MASES entheseal point counts, dactylitis counts, and the activity of psoriasis measured by PASI and body surface area (BSA).

Further secondary endpoints will evaluate the activity of axial involvement using the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI), quality of life and health/disability through Psoriatic Arthritis Impact of Disease (PsAID-12), Health Assessment Questionnaire-Disability Index (HAQ-DI), Dermatology Life Quality Index (DLQI), Ankylosing Spondylitis Quality of Life (ASQoL), and the Short Form (36) Health Survey (SF-36). Pain will be assessed using a visual analog scale (VAS). The trial will also measure the proportion of patients experiencing loss of MDA within 12 and 24 months after baseline, time to loss of MDA, and time needed to restore MDA after readjustment of the DMARD therapy in subjects who lost MDA within the intervention period. Biomarker levels and intervention-related events within the observation period of 24 months after baseline will also be monitored. Adverse events (AE), adverse reactions (AR), serious adverse events (SAE), serious adverse reactions (SAR), and suspected unexpected serious adverse reactions (SUSAR) will be recorded. Hand function will be evaluated using subjective measures such as SACRAH, DASH, and MHQshort, as well as objective measures like grip strength (lbf) and the Moberg pick-up test (s).