Phase 4 Multicenter Study Comparing Active Conventional Therapy with Biologic Agents and De-escalation Strategies in Early Rheumatoid Arthritis

The primary objective of this phase 4 study is to assess and compare the **proportion** of patients with early **rheumatoid arthritis** who achieve remission using active conventional therapy (ACT) versus three different biologic therapies. Additionally, the study aims to evaluate two alternative de-escalation strategies in patients who respond to first-line therapy. This objective is clinically relevant as it seeks to determine the most effective treatment approach for achieving remission in early rheumatoid arthritis, potentially guiding therapeutic decisions and improving patient outcomes.

The clinical trial focuses on individuals diagnosed with **Rheumatoid Arthritis**. The study population includes both male and female participants aged 18 years and older. Participants are required to be in good general health, as assessed by the principal investigator through medical history, laboratory profiles, physical examinations, chest X-rays, and 12-lead electrocardiograms conducted during the screening phase. The trial does not involve a vulnerable population. Participants must have a disease activity score (DAS28 CRP) greater than 3.2, with at least two swollen and two tender joints. The study does not specify the total number of participants, as this information was not provided by the sponsor. Lifestyle considerations such as diet and physical activity are not detailed in the available data. The selection criteria include the ability to self-administer subcutaneous injections or have a qualified person available to do so, and female participants of childbearing potential must adhere to specific birth control methods and have a negative pregnancy test at screening. The sponsor has not provided the total number of participants involved in the trial.

The clinical trial is designed as a **randomized**, open-label, blinded-assessor, phase 4 study aimed at evaluating the efficacy of active conventional therapy compared to three biologic treatments in patients with early **rheumatoid arthritis**. The trial also investigates two de-escalation strategies for patients who respond to initial treatment. The study is expected to run until December 31, 2030, with recruitment having commenced on December 14, 2012. Participants will be involved in the study for a maximum treatment period of 625 days, depending on their response to the treatment and adherence to the protocol.

Participants will undergo a series of study visits, beginning with a screening visit to confirm eligibility based on criteria such as age, diagnosis, and health status. The inclusion criteria require participants to be at least 18 years old, have a diagnosis of rheumatoid arthritis as per ACR/EULAR criteria, and meet specific clinical parameters such as DAS28 (CRP) > 3.2 and joint counts. Female participants of childbearing potential must use effective contraception and have a negative pregnancy test at screening. The primary efficacy outcome is the proportion of patients achieving remission at week 24, assessed by the Clinical Disease Activity Index (CDAI), with radiographic outcomes evaluated at 48 weeks.

Following the screening, participants will be randomized to receive either active conventional therapy or one of the biologic treatments. The trial includes regular follow-up visits to monitor treatment response, safety, and any adverse events. The end-of-study visit will assess the final outcomes and gather data on the long-term effects of the treatment strategies. Participants may be withdrawn from the study early if they experience significant adverse effects, fail to comply with the study protocol, or if the investigator deems it necessary for their safety.

The clinical trial involves several treatments, including both experimental and non-experimental medications. **Hydroxychloroquine sulfate** is administered orally in a pharmaceutical form identified as PHF00082MIG. The maximum daily dose is 5 mg/kg, with a total maximum dose of 21,875 mg/kg over a treatment period of 625 days. This chemical substance is used as a comparator in the study.

**Abatacept** is provided via subcutaneous injection in the pharmaceutical form PHF00231MIG. The maximum daily dose is 17.86 mg, with a total maximum dose of 78,125 mg over 625 days. Abatacept, a protein-based substance, serves as a test treatment in the trial.

**Azathioprine** is administered orally in the form PHF00170MIG. The maximum daily dose is 2.5 mg/kg, with a total maximum dose of 10,938 mg/kg over 625 days. This chemical substance is used as a comparator in the study.

**Sulfasalazine** is given orally in the form PHF00242MIG. The maximum daily dose is 2 g, with a total maximum dose of 8,750 g over 625 days. This chemical substance is used as a comparator in the study.

**Methotrexate sodium** is administered via subcutaneous injection in the form PHF00231MIG, with a maximum daily dose of 3.57 mg and a total maximum dose of 15,625 mg over 625 days. It is also administered orally in the form PHF00245MIG, with the same dosing schedule. Methotrexate sodium is used as an auxiliary treatment in the trial.

**Certolizumab pegol** is provided as a solution for injection in a pre-filled syringe, with a maximum daily dose of 14.29 mg and a total maximum dose of 62,400 mg over 625 days. This protein-based substance is used as a test treatment in the study.

**Leflunomide** is administered orally in tablet form, with a maximum daily dose of 20 mg and a total maximum dose of 87,500 mg over 625 days. This chemical substance is used as a comparator in the study.

**Tocilizumab** is administered in two forms: as a solution for injection in a pre-filled syringe with a maximum daily dose of 23.14 mg and a total maximum dose of 101,250 mg over 625 days, and as a concentrate for solution for infusion with a maximum daily dose of 0.29 mg/kg and a total maximum dose of 1,248 mg/kg over 625 days. Tocilizumab is used as a test treatment in the study.

**Betamethasone sodium phosphate** is administered orally in the form PHF00059MIG, with a maximum daily dose of 20 mg and a total maximum dose of 1,820 mg over 36 days. This chemical substance is used as an auxiliary treatment in the trial.

**Triamcinolone hexacetonide** is provided as a suspension for injection, with a maximum daily dose of 4 ml and a total maximum dose of 84 ml over 160 days. This chemical substance is used as a test treatment in the study.

Participant compliance with the dosing schedules is monitored throughout the trial to ensure adherence to the treatment protocols. The study aims to assess the efficacy of these treatments in achieving remission in patients with early rheumatoid arthritis, comparing active conventional therapy with various biologic treatments and de-escalation strategies.

The efficacy of the clinical trial will be assessed using specific primary endpoints. The primary efficacy outcome for Treatment Part 1 is the proportion of patients achieving remission at week 24 from baseline, as determined by the **CDAI** (Clinical Disease Activity Index). Additionally, the primary radiographic outcome will be the progression of the total Sharp van der Heijde score after 48 weeks from baseline. For Treatment Part 2, the primary efficacy outcome is the proportion of patients in remission according to the **CDAI**, measured 24 weeks after the dose was first reduced.