Evaluation of Proactive Therapeutic Drug Monitoring Versus Standard Care in Sustaining Disease Control in Rheumatoid Arthritis Patients on Subcutaneous Adalimumab

The primary objective of this study is to evaluate whether **proactive therapeutic drug monitoring (TDM)** is superior to the standard of care in maintaining sustained disease control without flares in patients with rheumatoid arthritis (RA) treated with subcutaneous tumor necrosis factor inhibitors (SC TNFi). This is clinically relevant as achieving sustained disease control is crucial for improving long-term outcomes and quality of life in RA patients.

Secondary objectives include:

• Comparing the effectiveness of proactive TDM to standard care on various outcome measures.
• Assessing the safety of proactive TDM.
• Evaluating whether proactive TDM influences drug survival, drug consumption, occurrence of anti-drug antibodies (ADAb), and serum drug levels.

The clinical trial involves a total of **19 participants** diagnosed with **rheumatoid arthritis**. The study population includes both male and female subjects, aged between 18 and 74 years. Participants are required to have a clinical diagnosis of rheumatoid arthritis and must be on stable therapy with a standard dose of a subcutaneous TNF inhibitor, specifically adalimumab, for a duration ranging from a minimum of 3 months to a maximum of 24 months. The participants are in a state of low disease activity or remission, as indicated by a DAS28-CRP score of less than 3.2, and have a medical indication for the continuation of treatment as determined by their treating physician. The trial does not include a vulnerable population, and all participants must be capable of understanding and signing an informed consent form. Lifestyle factors such as diet and physical activity are not specified as part of the selection criteria for this study.

The clinical trial is designed as a multi-center, open, randomized, parallel-group study with a duration of 18 months. The primary objective is to evaluate the efficacy of proactive therapeutic drug monitoring (TDM) compared to the standard of care in maintaining sustained disease control without flare-ups in adults with **rheumatoid arthritis** treated with a subcutaneous tumor necrosis factor inhibitor (TNFi). The trial involves the administration of **adalimumab**, a TNFi, in the form of a 40 mg solution for injection, delivered subcutaneously using pre-filled pens or syringes. The study will include participants aged 18 to 74 years who have been on stable therapy with a standard dose of subcutaneous TNFi for a minimum of 3 months and a maximum of 24 months, and who are in low disease activity or remission.

Participants will be randomly assigned to either the proactive TDM group or the standard care group. The trial will consist of several study visits, beginning with an inclusion (screening) visit to confirm eligibility based on the principal inclusion criteria, which include a clinical diagnosis of rheumatoid arthritis and the ability to provide informed consent. Follow-up visits will occur at 4, 8, 12, and 18 months to assess disease activity, time to disease flare, and monitor adverse events. The primary endpoint is sustained disease control over the 18-month follow-up period without flare, defined by specific criteria related to the Disease Activity Score using 28 joints and C-reactive protein (DAS28-CRP). Secondary endpoints include disease activity at specified intervals, time to disease flare, and drug-related outcomes such as drug survival and serum drug levels.

The expected length of participant involvement is up to 18 months, with conditions for early termination including the occurrence of a major change in treatment due to disease flare or withdrawal of consent. The trial is categorized as low intervention, as the investigational medicinal products (IMPs) are authorized and used according to their marketing authorization, with the monitoring procedure posing minimal additional risk compared to normal clinical practice. The trial is set to commence recruitment on June 1, 2024, with an estimated end date of December 31, 2027.

The clinical trial involves the administration of several **adalimumab**-based treatments, each formulated as a 40 mg solution for injection. These treatments are provided in various pharmaceutical forms, including pre-filled pens and pre-filled syringes, and are administered subcutaneously. The experimental medications include Hulio, Yuflyma, Humira, Hyrimoz, Libmyris, Idacio, AMGEVITA, Imraldi, and Hukyndra, all containing the active substance adalimumab. Each product is authorized for use in the European Union and is manufactured by different pharmaceutical companies, such as BIOSIMILAR COLLABORATIONS IRELAND LIMITED, CELLTRION HEALTHCARE HUNGARY KFT, ABBVIE DEUTSCHLAND GMBH & CO. KG, SANDOZ GMBH, STADA ARZNEIMITTEL AG, FRESENIUS KABI DEUTSCHLAND GMBH, AMGEN EUROPE B.V., and SAMSUNG BIOEPIS NL B.V.

Hulio 40 mg solution for injection is available in both pre-filled pens and pre-filled syringes. The pharmaceutical form is a solution for injection, and the route of administration is subcutaneous. The maximum daily dose is 40 mg, with a total treatment period of up to 18 months. The product is manufactured by BIOSIMILAR COLLABORATIONS IRELAND LIMITED.

Yuflyma 40 mg solution for injection is also available in pre-filled pens and pre-filled syringes. It is administered subcutaneously with a maximum daily dose of 40 mg. The treatment period can extend up to 18 months. CELLTRION HEALTHCARE HUNGARY KFT is the manufacturer of this product.

Humira 40 mg solution for injection is provided in both pre-filled pens and pre-filled syringes. The administration route is subcutaneous, with a maximum daily dose of 40 mg. The treatment duration is up to 18 months. This product is manufactured by ABBVIE DEUTSCHLAND GMBH & CO. KG.

Hyrimoz 40 mg solution for injection is available in pre-filled syringes and pre-filled pens. It is administered subcutaneously, with a maximum daily dose of 40 mg and a treatment period of up to 18 months. SANDOZ GMBH is the manufacturer of Hyrimoz.

Libmyris 40 mg solution for injection is provided in pre-filled pens. The administration is subcutaneous, with a maximum daily dose of 40 mg and a treatment period of up to 18 months. This product is manufactured by STADA ARZNEIMITTEL AG.

Idacio 40 mg solution for injection is available in pre-filled pens and pre-filled syringes. It is administered subcutaneously, with a maximum daily dose of 40 mg and a treatment period of up to 18 months. FRESENIUS KABI DEUTSCHLAND GMBH is the manufacturer of Idacio.

AMGEVITA 40 mg solution for injection is provided in pre-filled syringes and pre-filled pens. The administration route is subcutaneous, with a maximum daily dose of 40 mg and a treatment period of up to 18 months. This product is manufactured by AMGEN EUROPE B.V.

Imraldi 40 mg solution for injection is available in pre-filled pens and pre-filled syringes. It is administered subcutaneously, with a maximum daily dose of 40 mg and a treatment period of up to 18 months. SAMSUNG BIOEPIS NL B.V. is the manufacturer of Imraldi.

Hukyndra 40 mg solution for injection is provided in pre-filled syringes and pre-filled pens. The administration is subcutaneous, with a maximum daily dose of 40 mg and a treatment period of up to 18 months. This product is manufactured by STADA ARZNEIMITTEL AG.

Hefiya 40 mg solution for injection is available in pre-filled pens and pre-filled syringes. It is administered subcutaneously, with a maximum daily dose of 40 mg and a treatment period of up to 18 months. SANDOZ GMBH is the manufacturer of Hefiya.

Participant compliance with the dosing schedule is monitored throughout the trial to ensure adherence to the prescribed treatment regimen. The trial aims to assess the efficacy of proactive therapeutic drug monitoring compared to standard care in maintaining sustained disease control in adults with rheumatoid arthritis treated with subcutaneous tumor necrosis factor inhibitors.

The efficacy of the clinical trial will be assessed using both primary and secondary endpoints. The primary endpoint is the maintenance of sustained disease control without flare over an 18-month follow-up period in patients with rheumatoid arthritis treated with subcutaneous tumor necrosis factor inhibitors. A flare is defined as an increase in the Disease Activity Score using 28 joints-C-reactive protein (DAS28-CRP) by ≥ 1.2, or ≥ 0.6 if DAS28-CRP is already ≥ 3.2, along with ≥ 2 swollen joints upon examination of 44 joints, or a consensus between the participant and physician that a disease flare has occurred, necessitating a major change in treatment.

Secondary endpoints include the assessment of disease activity at 4, 8, 12, and 18 months, time to disease flare, the number and type of adverse events, drug survival, drug consumption, occurrence of anti-drug antibodies (ADAb), and serum drug levels. These parameters will be measured and collected at specified time points throughout the trial duration. The use of validated scales and laboratory tests will ensure the accuracy and reliability of the data collected. The trial aims to determine if proactive therapeutic drug monitoring is superior to the standard of care in maintaining disease control without flares.