Evaluation of Long-term Safety and Tolerability of Human Normal Immunoglobulin and Hyaluronidase (Human Recombinant) in Primary Immunodeficiency Diseases

The primary objective of this study is to evaluate the **long-term safety** and **tolerability** of TAK-881 in subjects with **Primary Immunodeficiency Diseases (PIDD)**. This is clinically relevant as it aims to ensure that the treatment is safe for prolonged use in managing PIDD, a group of disorders characterized by an impaired immune system, which can lead to increased susceptibility to infections and other health complications.

Secondary objectives include:

• Assessing infections in all subjects.
• Evaluating the long-term **immunogenicity** of TAK-881.
• Assessing IgG trough levels.
• Evaluating the treatment regimen with TAK-881.
• Evaluating infusion parameters.
• Assessing subject satisfaction with TAK-881 treatment in subjects aged ≥16 years.
• Assessing subject **HRQoL** while on TAK-881 treatment in subjects aged ≥12 years.
• Assessing treatment preferences for TAK-881 in subjects aged ≥12 years.
• Assessing **HRU** for subjects using TAK-881.
• Assessing infusion preparation time for TAK-881 by nurse/pharmacist/subject/caregiver recordings.

The clinical trial involves a total of **20 participants** diagnosed with **Primary Immunodeficiency Diseases**. The study population includes both male and female subjects, encompassing a diverse age range that includes children, adolescents, and adults. Participants were selected based on their completion of a prior study, TAK-881-3001, and their ability to comply with the study protocol. The trial includes a vulnerable population, indicating that special considerations are in place to ensure their safety and well-being. Participants' general health status is characterized by their underlying medical condition, and no specific lifestyle considerations such as diet or physical activity are highlighted. The study aims to evaluate the long-term safety and tolerability of TAK-881 in all subjects.

The clinical trial is designed to evaluate the long-term safety and tolerability of **TAK-881** in subjects with **Primary Immunodeficiency Diseases**. This is a phase 3, randomized, double-blind, controlled trial. The trial is expected to commence on April 18, 2025, and conclude by February 13, 2029. Participants will be involved in the study for a maximum treatment period of 121 days, during which they will receive **TAK-881** as a **solution for infusion** administered subcutaneously. The trial will utilize various devices, including the Qcore Sapphire Infusion Pump and Sapphire Administration tubing, all of which have CE marks.

The study will begin with an inclusion (screening) visit to confirm eligibility, which requires participants to have completed Study TAK-881-3001 and to provide informed consent. Following the screening, participants will undergo regular follow-up visits to monitor the occurrence of treatment-emergent adverse events (TEAEs) and any infusion-related issues. The primary endpoints include the occurrence of TEAEs and infusion-related complications. Secondary endpoints will assess efficacy, immunogenicity, pharmacokinetics, treatment regimen, infusion parameters, subject satisfaction, health-related quality of life, treatment preferences, and healthcare resource utilization.

The end-of-study visit will occur after the completion of the treatment period, where final assessments will be conducted. Participants may be withdrawn from the study early if they experience significant adverse events or are unable to comply with the study protocol. The trial aims to provide comprehensive data on the safety profile of **TAK-881** and its impact on the quality of life and treatment satisfaction of individuals with **Primary Immunodeficiency Diseases**.

The clinical trial involves the administration of the experimental medication **TAK-881**, which is a **solution for infusion**. This investigational product contains two active substances: **human normal immunoglobulin** and **hyaluronidase (human recombinant)**. The pharmaceutical form of TAK-881 is a solution intended for subcutaneous administration. The maximum daily dose is 120 grams, with a total maximum dose of 7080 grams over a treatment period of 121 days. The administration of TAK-881 is facilitated by the use of specific medical devices, including the Qcore Sapphire Infusion Pump and Sapphire Administration tubing, which are equipped with CE marks to ensure compliance with safety standards.

In addition to the experimental treatment, the study may involve the use of standard medical devices such as syringes and needles, including the 309653 BD 50ml Luer Lock syringe and the Koru 24G Subcutaneous Needle set, both of which are also CE marked. These devices are used to ensure accurate dosing and administration of the investigational product. Participant compliance with the dosing schedule is monitored throughout the study to ensure adherence to the protocol and to evaluate the long-term safety and tolerability of TAK-881 in subjects with primary immunodeficiency diseases.

Efficacy in this clinical trial will be assessed using several secondary endpoints. These include the **annualized rate of all infections**, the annualized rate of acute serious bacterial infections (ASBIs), the annualized rate of episodes of fever, the time to first ASBI, and the duration of infections. Additionally, the trial will evaluate the occurrence of positive binding and neutralizing antibodies to recombinant human hyaluronidase (rHuPH20) as part of the immunogenicity assessment. Pharmacokinetic parameters will be measured by assessing the trough level of total immunoglobulin G (IgG).

The treatment regimen will be evaluated by the dose and treatment interval of TAK-881. Infusion parameters will be assessed, including the number of infusions per month, the number of infusion sites per month and per infusion, the duration of infusions, monthly infusion time, maximum tolerated infusion rate per site, infusion volume per site, and the physical location of infusion. Subject satisfaction will be evaluated using the Treatment Satisfaction Questionnaire for Medication (TSQM-9), and health-related quality of life will be assessed via the EQ-5D-5L questionnaire. Treatment preferences will be measured by a disease-specific questionnaire.

Healthcare resource utilization will be monitored by recording days not able to go to school, work, daycare, or perform normal daily activities due to infections or their treatment, days on antibiotics, number of hospitalizations, indication for hospitalization, days hospitalized, and number of acute physician visits due to infection or other illnesses. Infusion preparation time will be measured by healthcare professionals and subjects or caregivers according to guidelines in the Pharmacy Manual/Site Infusion Manual and the Subject Infusion Manual, respectively.