Evaluation of a Personalized Treatment Strategy Versus Standard Care in Rheumatoid Arthritis Using Methotrexate, Golimumab, and Hydroxychloroquine Sulfate

The primary objective of the PRIMERA trial is to assess the clinical effectiveness of a tailor-made management approach in patients with **rheumatoid arthritis**. This is evaluated by comparing the proportion of patients using a b- or tsDMARD after 10 months of treatment and measuring disease activity using the Disease Activity Score (DAS) over time. The approach is considered superior if it achieves (very) low disease activity more rapidly without increasing the use of expensive b- or tsDMARDs. Additionally, the primary outcome for cost-effectiveness is determined by the incremental cost-effectiveness ratio (ICER), which compares the difference in costs to incremental benefits between the two management strategies. This is clinically relevant as it aims to optimize treatment efficacy while minimizing costs, potentially improving patient outcomes and healthcare resource allocation.

Secondary objectives include: - Investigating differences in patient-reported outcomes such as self-reported disease activity, functional ability, morning stiffness, general health, pain, fatigue, quality of life, worker productivity, and social participation between the management approaches. - Evaluating whether patient satisfaction, compliance, and participation are enhanced with the tailor-made approach compared to routine care. - Exploring the potential for further individualization of the tailor-made approach by incorporating biomarker(s).

The clinical trial involves participants diagnosed with **rheumatoid arthritis** according to the 2010 criteria. The study population includes both male and female subjects, aged 18 years and older. Participants are newly diagnosed and have not previously been treated with DMARDs. The trial does not include a vulnerable population. The sponsor has not provided information regarding the total number of participants. The selection criteria focus on individuals who are DMARD-naive, ensuring that the study evaluates the effectiveness of treatment in a population that has not been influenced by prior medication. Lifestyle factors such as diet, physical activity, and habits are not specified in the available data.

The clinical trial is designed to evaluate the effectiveness of a personalized management approach for patients with **rheumatoid arthritis** compared to routine care. This is a multicenter, open-label, randomized controlled trial. The trial aims to assess both clinical and cost-effectiveness outcomes over a period of approximately 48 months, with an estimated end date of March 6, 2025. The primary clinical outcomes include the proportion of patients using a biological or targeted synthetic disease-modifying antirheumatic drug (b- or tsDMARD) after 10 months and the disease activity score (DAS) over time. The cost-effectiveness will be measured using the incremental cost-effectiveness ratio (ICER).

Participants will undergo a series of study visits, beginning with an inclusion visit to confirm eligibility based on criteria such as being newly diagnosed and DMARD-naive, and aged 18 years or older. Follow-up visits will be scheduled to monitor disease activity, treatment response, and other health parameters. These visits will include assessments of disease activity states, biomarker levels, self-reported disease activity, morning stiffness, general health, fatigue, pain, functional ability, quality of life, patient satisfaction, compliance, and worker productivity. The end-of-study visit will conclude the participant's involvement, summarizing the outcomes and any adverse events.

The expected length of participant involvement is up to 40 weeks, depending on the treatment regimen. Conditions that may lead to early termination from the study include non-compliance with the study protocol, withdrawal of consent, or adverse events that compromise participant safety. The trial will adhere to safety monitoring protocols, including laboratory tests at fixed intervals, in accordance with Dutch guidelines. The trial's design ensures that all prescribed medications are approved and used according to their labels, with generic commercial supplies utilized for all drugs involved in the study.

The clinical trial involves the administration of several experimental medications, each with specific pharmaceutical forms, dosages, and routes of administration. **Methotrexate** is provided as 2.5 mg film-coated tablets, administered orally. The maximum daily dose is 3.6 mg, with a total maximum dose of 1000 mg over a treatment period of up to 40 weeks. Participant compliance is monitored through regular assessments.

**Simponi**, containing the active substance **golimumab**, is administered as a 50 mg solution for injection in a pre-filled syringe. The route of administration is subcutaneous injection, with a maximum daily dose of 3.6 mg and a total maximum dose of 600 mg over a 24-week period.

**Hydroxychloroquine sulfate** is provided in 200 mg film-coated tablets, taken orally. The maximum daily dose is 400 mg, with a total maximum dose of 400 mg over a 40-week treatment period. Compliance is ensured through scheduled follow-ups.

**Cimzia**, containing **certolizumab pegol**, is administered as a 200 mg solution for injection in a pre-filled syringe. The subcutaneous injection route is used, with a maximum daily dose of 14.29 mg and a total maximum dose of 3000 mg over 24 weeks.

**Depo-Medrol**, with the active substance **methylprednisolone acetate**, is provided as an 80 mg/2 ml suspension for injection. It is administered via intramuscular injection, with a maximum daily dose of 120 mg and a total maximum dose of 720 mg over a 6-week period.

**Leflunomide** is available as 20 mg film-coated tablets, taken orally. The maximum daily dose is 20 mg, with a total maximum dose of 20 mg over a 40-week treatment period. Participant adherence is monitored through regular check-ins.

**Enbrel**, containing **etanercept**, is administered as a 50 mg solution for injection in a pre-filled syringe. The subcutaneous injection route is used, with a maximum daily dose of 7.14 mg and a total maximum dose of 1200 mg over 24 weeks.

**Humira**, with the active substance **adalimumab**, is provided as a 40 mg solution for injection in a pre-filled syringe. It is administered subcutaneously, with a maximum daily dose of 3 mg and a total maximum dose of 480 mg over a 24-week period.

**Sulfasalazine** is available in 500 mg tablets, taken orally. The maximum daily dose is 2000 mg, with a total maximum dose of 560000 mg over a 40-week treatment period. Compliance is tracked through periodic evaluations.

**Jyseleca**, containing **filgotinib**, is provided as 200 mg film-coated tablets, administered orally. The maximum daily dose is 200 mg, with a total maximum dose of 200 mg over a 28-week period.

**Kenacort-A 40**, with the active substance **triamcinolone acetonide**, is administered as a 40 mg/ml suspension for injection. The route of administration is intramuscular injection, with a maximum daily dose of 80 mg and a total maximum dose of 500 mg over a 6-week period.

**Remicade**, containing **infliximab**, is provided as a 100 mg powder for concentrate for solution for infusion. It is administered intravenously, with a maximum daily dose of 5 mg/kg and a total maximum dose of 5 mg/kg over a 24-week period. Compliance is ensured through scheduled infusions and monitoring.

The efficacy of the clinical trial will be assessed using a combination of primary and secondary endpoints. The primary outcomes for clinical effectiveness include the difference in the proportion of patients using a b- or tsDMARD after 10 months of treatment and the measurement of disease activity over time using the **Disease Activity Score (DAS)**. The primary outcome for cost-effectiveness will be evaluated through the incremental cost-effectiveness ratio (ICER), which compares the difference in costs to incremental benefits between the management approaches.

Secondary endpoints will provide additional insights into the efficacy of the treatment. These include disease activity states at 10 months, changes in biomarker levels to predict treatment response, and self-reported disease activity using the Routine Assessment of Patient Index Data 3 (RAPID3). Other parameters include morning stiffness severity and duration measured with a 10-point Likert scale, general health and fatigue assessed with a visual analogue scale (VAS), pain evaluated using the Generalized Pain Questionnaire (GPQ) and PainDetect, and functional ability measured with the Health Assessment Questionnaire (HAQ). Quality of life will be assessed using the Dutch EuroQol questionnaire with 5 dimensions (EQ-5D) with 5 levels.

Additional assessments will include patient satisfaction, compliance, and participation measured with the Treatment Satisfaction Questionnaire for Medication (TSQM), the Medication Adherence Report Scale (MARS-5), and the 9-Item Shared Decision Making Questionnaire (SDMQ9). The Impact on Participation and Autonomy questionnaire (IPAQ) will focus on autonomy and participation of patients with chronic conditions. Worker productivity will be evaluated using the Work Productivity and Activity Impairment (WPAI) questionnaire, which includes measures of presentism and absenteeism.