A Randomized Controlled Trial Comparing Azathioprine and Methotrexate in Combination with Adalimumab for Endoscopic Response in Crohn's Disease Patients

The primary objective of this study is to compare the **endoscopic response** to azathioprine (AZA) and methotrexate (MTX) in combination with adalimumab in patients with **Crohn's Disease** (CD). This is clinically relevant as endoscopic response is a critical marker for assessing the effectiveness of treatment in reducing intestinal inflammation and improving patient outcomes in CD.

Secondary objectives include:

• Comparing AZA to MTX in combination therapy with adalimumab on clinical efficacy, specifically remission and response.
• Evaluating the pharmacokinetics of adalimumab when used with AZA versus MTX in CD.
• Assessing the impact on the level of inflammatory biomarkers.
• Comparing the impact on CD-related disability and quality of life.
• Evaluating the effect on the natural history of CD, including surgeries and hospitalizations.
• Comparing the safety profiles of AZA and MTX in combination with adalimumab.

The clinical trial involves participants diagnosed with **Crohn's Disease**. The study population includes both male and female subjects, all of whom are over the age of 18. Participants are required to have had Crohn's Disease for at least six weeks and must exhibit clinically active disease with a Crohn's Disease Activity Index (CDAI) greater than 150. Additionally, active inflammation must be confirmed by endoscopy, with a Simple Endoscopic Score for Crohn's Disease (SES-CD) of 6 or more, or 4 or more in cases of isolated ileum disease, at baseline. The trial specifically targets individuals who have not responded to conventional therapies such as steroids or immunosuppressants, or those who are intolerant to or have medical contraindications for such treatments, and are initiating treatment with adalimumab. Participants are recruited from centers within the GETAID network. Fertile men and women of childbearing potential are required to use adequate contraception methods as per the study drug's Summary of Product Characteristics (SMPCs). The sponsor has not provided information regarding the total number of participants in the trial.

The clinical trial is designed as an **open-label randomized controlled trial** to evaluate the efficacy of **azathioprine** compared to **methotrexate** in combination with **adalimumab** for patients with **Crohn's Disease**. The primary objective is to assess the endoscopic response, defined as a decrease of at least 50% in the SES-CD score at week 26 compared to baseline. The trial will span an estimated duration from September 2022 to September 2027, with a maximum treatment period of 104 weeks for each participant.

Participants will be randomly assigned to receive either azathioprine or methotrexate in combination with adalimumab. The trial includes several key visits: an initial screening visit to confirm eligibility, regular follow-up visits to monitor clinical response and remission, and an end-of-study visit to assess the overall outcomes. The inclusion criteria require participants to be adults with clinically active Crohn's Disease, evidenced by a CDAI score greater than 150 and active inflammation confirmed by endoscopy. Participants must have not responded to conventional therapies or have contraindications to such treatments.

The expected length of participant involvement is up to 104 weeks, with conditions for early termination including significant adverse events, lack of compliance, or withdrawal of consent. Secondary endpoints include clinical response and remission at each visit, corticosteroid-free remission at specified weeks, and the necessity for adalimumab optimization. Additional assessments will include changes in IBD-Q, IBD-Disability index, C-reactive protein levels, and calprotectin levels at various intervals throughout the study. The trial will also monitor for CD-related hospitalizations, surgeries, and adverse events.

The clinical trial involves the administration of **Methotrexate**, marketed under the name METOJECT 25 mg/0.5 ml, as a **solution for injection** in a pre-filled syringe. This medication is administered via **subcutaneous use**. The maximum daily dose is 25 mg, with a total maximum dose of 2600 mg over a treatment period of 104 weeks. Methotrexate is a chemical substance and is not formulated for pediatric use. The pharmaceutical form is a solution for injection, and the product is authorized in France by MEDAC GESELLSCHAFT FÜR KLINISCHE SPEZIALPRÄPARATE MBH (WEDEL).

**Azathioprine**, marketed as IMUREL 25 mg, is provided in the form of a **film-coated tablet**. The administration route is **oral use**. The maximum daily dose is 2.5 mg/kg, with a total maximum dose of 1820 mg/kg over the same treatment period of 104 weeks. Azathioprine is also a chemical substance and is not intended for pediatric use. This product is authorized in France and is manufactured by ASPEN PHARMA TRADING LIMITED.

**Adalimumab**, marketed as Humira 20 mg, is available as a **solution for injection** in a pre-filled syringe. It is administered via **subcutaneous use**. The maximum daily dose is 160 mg, with a total maximum dose of 4240 mg over 104 weeks. Adalimumab is a protein-based substance and is not formulated for pediatric use. The product is authorized in the European Union and is produced by ABBVIE DEUTSCHLAND GMBH & CO. KG.

The trial aims to compare the endoscopic response of azathioprine and methotrexate when used in combination with adalimumab in patients with **Crohn's Disease**. The study is designed as an open-label randomized controlled trial, with azathioprine and methotrexate serving as test treatments, and adalimumab as a standard-of-care therapy. Participant compliance will be monitored throughout the study to ensure adherence to the dosing schedules.

The efficacy of the clinical trial comparing azathioprine to methotrexate in combination with adalimumab for the treatment of **Crohn's Disease** will be assessed using both primary and secondary endpoints. The primary endpoint is the endoscopic response, defined as a decrease of at least 50% in the Simple Endoscopic Score for Crohn's Disease (SES-CD) at week 26 compared to baseline. This will be measured through endoscopic evaluations conducted at specified intervals.

Secondary endpoints include a variety of clinical and laboratory measures. These encompass clinical response and remission at each visit, corticosteroid-free clinical remission at weeks 12, 26, 52, 78, and 104, and the necessity for adalimumab optimization during follow-up. Additionally, the trial will monitor the withdrawal of azathioprine, methotrexate, and adalimumab, as well as trough serum levels and antibodies to adalimumab at specified weeks. Changes in the Inflammatory Bowel Disease Questionnaire (IBD-Q) and IBD-Disability index, C-reactive protein (CRP) levels, and calprotectin levels will be assessed at multiple timepoints, including weeks 0, 12, 26, 52, 78, and 104.

Further secondary endpoints include endoscopic remission, defined as SES-CD less than 3 and ulcer-free endoscopy at week 26, deep remission at week 26, and the occurrence of Crohn's Disease-related hospitalizations and surgeries during follow-up. The trial will also document any adverse events occurring throughout the study period. These efficacy parameters will be collected and analyzed according to the trial's protocol to determine the comparative effectiveness of the treatment regimens.