Evaluation of Human Normal Immunoglobulin Dosing on Lung Disease Progression in Patients with Primary Antibody Deficiency

The primary objective of this study is to demonstrate the protective value and assess the cost-effectiveness of higher dosing of **immunoglobulin (Ig)** replacement therapy on the progression of lung disease in patients with **primary antibody deficiency (PAD)**. This is clinically relevant as it aims to optimize treatment strategies for PAD, potentially reducing the progression of pulmonary complications and improving patient outcomes.

Secondary objectives include evaluating the following:

• The incidence of symptomatic lower pulmonary infections in PAD patients receiving high versus standard Ig replacement therapy dosing.
• The number of physician-diagnosed lower respiratory tract infections in patients with high versus standard Ig replacement therapy dosing.
• The number and duration of hospital admissions for pulmonary complications, including exacerbations of bronchiectasis.
• Outcomes of pulmonary function tests, specifically Total Lung Capacity (TLC), Forced Expiratory Volume after 1 second (FEV1), and CO diffusion, at baseline and after two years in all patients.
• The number of days missed from work or school in patients with high versus standard Ig replacement therapy dosing.
• Total therapeutic and preventive costs associated with the different dosing regimens.

The clinical trial involves participants diagnosed with **Primary Antibody Deficiency**, including conditions such as unclassified antibody deficiency, IgA deficiency, specific polysaccharide antibody deficiency, IgG subclass deficiency, common variable immunodeficiency, and agammaglobulinemia. The study population comprises both male and female subjects, aged between 8 and 60 years, who are either indicated for or currently receiving immunoglobulin replacement therapy. Participants are required to have a current IgG dosing regimen of 0.25 to 0.6 grams per kilogram every 3 to 4 weeks and must be under the care of a physician at one of the participating centers. The trial includes a vulnerable population, and written informed consent is mandatory. The sponsor has not provided information regarding the total number of participants. Lifestyle factors such as diet and physical activity are not specified in the available data.

The clinical trial is designed to evaluate the protective value and cost-effectiveness of higher immunoglobulin (Ig) dosing on the progression of lung disease in patients with **primary antibody deficiency**. This trial is structured as a randomized, double-blind, controlled study, ensuring that neither the participants nor the researchers know which treatment the participants are receiving, thereby minimizing bias. The trial is expected to commence on July 15, 2024, and conclude by June 1, 2026, with an overall duration of approximately two years.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as age (8-60 years), diagnosis of primary antibody deficiency, and current IgG dosing. Following the screening, participants will be randomly assigned to either the standard or higher Ig replacement therapy dosing group. Regular follow-up visits will be scheduled to monitor the participants' health status, collect data on respiratory tract infections, pulmonary symptoms, and quality of life, and measure IgG trough levels. The primary endpoint is the difference in mean airway disease (AD) and interstitial lung disease (ILD) scores between the two groups over the two-year period, as measured by CT scanning.

The expected length of participant involvement is the full duration of the trial, approximately two years, unless conditions arise that necessitate early termination. Such conditions may include adverse events, serious adverse events, or suspected unexpected serious adverse reactions, which will be monitored by an independent entity. Participants may also be withdrawn if they no longer meet the inclusion criteria or if they choose to withdraw consent. The trial aims to provide valuable insights into the management of lung disease in primary antibody deficiency, with secondary endpoints including the number of respiratory infections, days missed from work or school, and total health costs.

The clinical trial involves the administration of several **experimental medications** containing **human normal immunoglobulin**. The first medication, Nanogam 100 mg/ml, is a **solution for infusion** intended for **intravenous** administration. The dosage is set at a maximum of 800 mg/kg per day, with a total maximum dose of 800 mg/kg. The treatment period is capped at 1,000,000 time units, ensuring a controlled and monitored administration process. This product is manufactured by Prothya Biosolutions Netherlands B.V. and is not a pediatric formulation.

HyQvia 100 mg/ml is another **solution for infusion**, but it is designed for **subcutaneous** use. The dosing parameters are similar to Nanogam, with a maximum daily dose of 800 mg/kg and a total maximum dose of 800 mg/kg. The treatment duration is also set at 1,000,000 time units. This product is developed by Baxalta Innovations GmbH and is not intended for pediatric use.

Privigen 100 mg/ml, a **solution for infusion**, is administered **intravenously**. It follows the same dosing guidelines as the previous medications, with a maximum daily and total dose of 800 mg/kg. The treatment period is consistent with the other products, set at 1,000,000 time units. CSL Behring GmbH is responsible for its production, and it is not formulated for pediatric patients.

KIOVIG 100 mg/ml is also a **solution for infusion** for **intravenous** administration. The dosing and treatment period are identical to those of Privigen, with a maximum of 800 mg/kg per day and a total dose of 800 mg/kg over 1,000,000 time units. This product is manufactured by Takeda Manufacturing Austria AG and is not a pediatric formulation.

Gammanorm, 165 mg/ml, is a **solution for injection** intended for **subcutaneous** administration. The dosing regimen is consistent with the other medications, with a maximum daily and total dose of 800 mg/kg. The treatment period remains at 1,000,000 time units. Octapharma Benelux S.A. produces this medication, and it is not designed for pediatric use.

CUTAQUIG 165 mg/mL is a **solution for injection** for **subcutaneous** use. It follows the same dosing guidelines, with a maximum daily and total dose of 800 mg/kg, and a treatment period of 1,000,000 time units. This product is developed by Octapharma France and is not intended for pediatric patients.

GAMMAGARD S/D 5.0 g is a **solution for infusion** administered **intravenously**. The dosing and treatment period are consistent with the other medications, with a maximum of 800 mg/kg per day and a total dose of 800 mg/kg over 1,000,000 time units. Baxalta Innovations GmbH is responsible for its production, and it is not a pediatric formulation.

Hizentra 200 mg/ml is a **solution for subcutaneous injection**. The dosing regimen is similar to the other medications, with a maximum daily and total dose of 800 mg/kg. The treatment period is set at 1,000,000 time units. CSL Behring GmbH produces this medication, and it is not designed for pediatric use.

Octagam 10% is a **solution for infusion** for **intravenous** administration. It follows the same dosing guidelines as the previous medications, with a maximum daily and total dose of 800 mg/kg. The treatment period remains at 1,000,000 time units. Octapharma GmbH is responsible for its production, and it is not intended for pediatric patients.

Cuvitru 200 mg/ml is a **solution for subcutaneous injection**. The dosing differs slightly, with a maximum daily dose of 150 mg/kg and a total maximum dose of 1000 mg/kg. The treatment period is consistent with the other products, set at 1,000,000 time units. Baxalta Innovations GmbH manufactures this medication, and it is not a pediatric formulation.

Efficacy in this clinical trial will be assessed using both primary and secondary endpoints. The primary endpoint involves measuring the difference in mean Airway Disease (AD) and Interstitial Lung Disease (ILD) scores, as determined by CT scanning, between baseline (t=0) and two years (t=2 years) in patients receiving standard versus higher immunoglobulin (Ig) replacement therapy dosing. This will provide insight into the progression of lung disease in patients with Primary Antibody Deficiency (PAD) under different dosing regimens.

Secondary endpoints include a variety of parameters to comprehensively evaluate the impact of the treatment. These include the number of upper and lower respiratory tract infections, such as sino-pulmonary disease, otitis, and pneumonia, recorded before and during the study using study Case Report Forms (CRFs). Pulmonary symptoms will be monitored daily over two periods of two months using a diary that participants can directly enter into the Castor system. Additionally, days missed from school and work due to infections will be measured using the Productivity Cost Questionnaire (PCQ) instrument. Quality of life will be assessed with the EQ-5D questionnaire.

Further assessments will include Ig dosing and IgG trough levels in both the intervention and control groups, as well as total health costs, which encompass costs for healthcare professional visits, medication, hospitalizations, imaging, and biochemical investigations, collected from electronic patient files. The immunological laboratory phenotype will also be collected from electronic patient files. Adverse events, including Serious Adverse Events (SAEs) and Suspected Unexpected Serious Adverse Reactions (SUSARs), will be reported and monitored by an independent monitor to ensure patient safety throughout the trial.