Efficacy and Safety of Birtamimab with Standard Care versus Placebo in Mayo Stage IV Light Chain Amyloidosis: A Phase 3 Randomized, Double-Blind Study

The primary objective of this study is to evaluate the **efficacy** of birtamimab plus standard of care compared to placebo plus standard of care in Mayo Stage IV subjects with Light Chain (AL) Amyloidosis. This will be assessed by measuring the time to all-cause mortality, which is clinically relevant as it directly impacts patient survival outcomes. Additionally, the study aims to assess the long-term **safety** of birtamimab plus standard of care in the same patient population.

Secondary objectives include evaluating the effects of birtamimab plus standard of care compared to placebo plus standard of care on:

• Change from baseline to Month 9 in the 6-Minute Walk Test (6MWT) distance.
• Change from baseline to Month 9 in health-related quality of life using the Short Form-36 questionnaire Version 2 (SF-36v2).

The clinical trial involves a total of **63 participants** diagnosed with **Light Chain (AL) Amyloidosis**, specifically those classified as Mayo Stage IV. The study population includes both male and female subjects, aged 18 years and older, who are newly diagnosed and treatment-naive with cardiac involvement. Participants were selected based on a confirmed diagnosis of AL amyloidosis, with specific cardiac biomarkers such as NT-proBNP ≥ 1800 pg/mL and Troponin-T ≥ 0.025 ng/mL, or high sensitivity cardiac troponin T ≥ 40 ng/L, and dFLC ≥ 18 mg/dL. The trial includes individuals who are planned to receive first-line chemotherapy containing bortezomib administered subcutaneously on a weekly basis. The study population is considered vulnerable, and the selection criteria ensure that participants are legally able to provide consent according to local regulations. Lifestyle factors such as diet and physical activity are not specified in the available data.

The clinical trial is a **Phase 3**, randomized, double-blind, placebo-controlled study designed to evaluate the efficacy and safety of **birtamimab** plus standard of care compared to placebo plus standard of care in subjects with Mayo Stage IV **Light Chain (AL) Amyloidosis**. The primary objective is to assess the time to all-cause mortality during the double-blind phase. Secondary endpoints include changes from baseline to Month 9 in the 6-minute walk test (6MWT) distance and the Physical Component Summary (PCS) score of the SF-36v2. The trial is expected to conclude by June 2027, with recruitment having commenced in October 2021.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as age, diagnosis of AL amyloidosis, and cardiac involvement. The trial will include multiple follow-up visits to monitor the participants' health status and response to treatment. The end-of-study visit will occur at the conclusion of the trial or upon early termination. The expected duration of participant involvement is until the end of the study, unless early termination is warranted due to adverse events, withdrawal of consent, or other protocol-specified reasons.

The trial involves the administration of birtamimab intravenously, with the standard of care including **bortezomib** administered subcutaneously. **Sodium chloride** is used as an isotonic solution in the trial. Participants are required to be newly diagnosed and treatment-naive for AL amyloidosis, with specific cardiac biomarkers confirming Mayo Stage IV status. The study is not categorized as low intervention and is conducted under rigorous conditions to ensure the validity and reliability of the results.

The clinical trial involves the administration of **Bortezomib**, a **proteasome inhibitor** used as part of the standard-of-care therapy for patients with AL amyloidosis. Bortezomib is provided in the form of a **powder for solution for injection**. The route of administration is via **injection**, with a maximum daily dose of 1.6 mg/m². The treatment period is set to a maximum of 9999 days, ensuring long-term administration as required by the study protocol. Bortezomib is recognized as a standard component of the Cyclophosphamide, Bortezomib, and Dexamethasone (CyBorD) regimen, although AL amyloidosis is not an approved indication in the Summary of Product Characteristics (SmPC).

**Birtamimab** is the experimental medication under investigation in this trial. It is a **biological/biotechnological** product, specifically a humanized IgG1 kappa antibody targeting serum amyloid A and AL amyloid. Birtamimab is supplied as a **powder for solution for infusion** and is administered via **intravenous infusion**. The maximum daily dose is 24 mg/kg, with the treatment period also extending up to 9999 days. Birtamimab is being evaluated for its efficacy and safety in combination with standard-of-care therapy compared to a placebo in Mayo Stage IV subjects with AL amyloidosis.

**Sodium Chloride** is used as an auxiliary treatment in the study. It is provided as a **solution for infusion** and administered intravenously. Sodium Chloride serves as an **isotonic solution** and is not subject to a specific dosing schedule or maximum daily dose within the context of this trial. Its role is primarily supportive, ensuring proper hydration and electrolyte balance during the administration of the investigational and standard-of-care treatments.

The efficacy of the investigational treatment in this clinical trial will be assessed by evaluating the **time to all-cause mortality** during the Double-blind Phase. This primary endpoint will provide a direct measure of the treatment's impact on survival in subjects with Mayo Stage IV **AL amyloidosis**. Secondary endpoints include the change from baseline to Month 9 in the 6-Minute Walk Test (6MWT) distance, measured in meters, and the change in the Physical Component Summary (PCS) score of the SF-36v2, a validated health survey instrument. These secondary endpoints will assess functional capacity and quality of life, respectively.

Data collection for these endpoints will occur at specified timepoints, with the primary endpoint being monitored continuously throughout the Double-blind Phase. The secondary endpoints will be evaluated at baseline and at Month 9 of the Double-blind Phase. The 6MWT will be conducted according to standardized protocols to ensure consistency and reliability of the distance measurements. The SF-36v2 will be administered to capture patient-reported outcomes related to physical health. The analysis of these efficacy parameters will involve statistical methods appropriate for time-to-event data and changes from baseline, ensuring robust evaluation of the treatment's efficacy.