Phase 3 Multicentre Study on Subcutaneous Human Normal Immunoglobulin (Newnorm) for Primary Immunodeficiency Disease

Trial ID: 2024-511231-94-00
Protocol: NORM-01
Sponsor: Octapharma Pharmazeutika Produktionsgesellschaft mbH

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Diseases & Conditions

Primary immunodeficiency syndrome

Objectives

The primary objective of this study is to evaluate the **efficacy** of Newnorm in preventing serious bacterial infections (SBIs) in patients with primary immunodeficiency diseases. Additionally, the primary pharmacokinetic (PK) objective is to confirm that weekly subcutaneous dosing of Newnorm, adjusted by a dose conversion factor of 1.37 for patients previously treated with an intravenous immunoglobulin (IVIG) product, results in average total immunoglobulin G (IgG) levels that are statistically non-inferior to 3- or 4-weekly IVIG dosing. This is clinically relevant as it aims to establish Newnorm as a viable alternative to traditional IVIG therapy, potentially offering more consistent IgG levels and improved patient outcomes.

Secondary objectives include:

Assessing the efficacy of Newnorm in infection control by comparing infection rates, time to resolution, antibiotic use, hospitalizations, episodes of fever, and days lost from work or educational settings with historical data.
Evaluating the effect of Newnorm on quality of life (QoL).
Assessing the tolerability and safety of Newnorm.
Describing the PK characteristics of Newnorm and comparing the minimum (trough) and maximum (peak) systemic levels on weekly dosing of Newnorm with 3- or 4-weekly IVIG dosing.

These secondary objectives aim to provide a comprehensive understanding of Newnorm's impact on patient health and its potential advantages over existing treatments.

Participants

The clinical trial involves a total of **22 participants** diagnosed with **Primary Immunodeficiency Disease (PID)**, as defined by the European Society of Immunodeficiencies (ESID) and the Pan American Group for Immune Deficiency (PAGID). The study population includes both male and female subjects, ranging in age from **2 to 75 years**. Participants were selected based on their requirement for immunoglobulin replacement therapy due to hypogammaglobulinaemia or agammaglobulinaemia, with a stable treatment regimen of intravenous or subcutaneous immunoglobulin prior to the study. The trial includes individuals who have maintained a trough level of immunoglobulin G (IgG) of at least 5 g/L. The study population is characterized by a willingness to comply with all protocol aspects, including blood sampling. The trial does not specify any particular lifestyle considerations such as diet or physical activity. The inclusion of a vulnerable population is noted, indicating careful ethical considerations in the selection process.

Plans and Procedures

The clinical trial is a **Phase 3** study designed to evaluate the pharmacokinetics, efficacy, tolerability, and safety of subcutaneous human immunoglobulin (Newnorm) in patients with **primary immunodeficiency diseases**. This is a prospective, open-label, single-arm, multicentre trial. The primary objective is to assess the efficacy of Newnorm in preventing serious bacterial infections (SBIs) and to confirm that weekly subcutaneous dosing results in average total immunoglobulin G (IgG) levels that are statistically non-inferior to 3- or 4-weekly intravenous immunoglobulin (IVIG) dosing. The trial is expected to last until September 2025, with recruitment having started in July 2021.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as age (2 to 75 years), documented diagnosis of primary immunodeficiency, and stable treatment history. Following the screening, participants will receive weekly subcutaneous infusions of Newnorm, with regular follow-up visits to monitor efficacy and safety outcomes. The primary endpoint is the rate of SBIs per person-year on treatment, analyzed over a 52-week efficacy period. Secondary endpoints include the rate of infections, use of antibiotics, hospitalizations due to infection, and quality of life assessments.

The expected length of participant involvement is approximately one year, with conditions for early termination including non-compliance with the protocol, adverse events, or withdrawal of consent. Participants must be willing to comply with all aspects of the protocol, including blood sampling, for the duration of the study. The study aims to provide comprehensive data on the use of Newnorm in managing primary immunodeficiency diseases, contributing to the understanding of its role in preventing serious infections in this patient population.

Treatment

The clinical trial involves the administration of **Newnorm**, a **solution for infusion** containing **human normal immunoglobulin** as the active substance. This investigational product is manufactured by OCTAPHARMA AG and is classified under the ATC code J06BA01, which pertains to **immunoglobulins, normal human, for extravascular administration**. The pharmaceutical form of Newnorm is a solution for infusion, and it is administered via the **subcutaneous route**. The dosing regimen involves a maximum daily dose of 400 mg/kg, with the treatment period not exceeding one day. The study aims to evaluate the pharmacokinetics, efficacy, tolerability, and safety of subcutaneous human immunoglobulin in patients with primary immunodeficiency diseases. The primary efficacy objective is to assess the prevention of serious bacterial infections, while the pharmacokinetic objective is to confirm that weekly subcutaneous dosing results in average total immunoglobulin G levels that are statistically non-inferior to 3- or 4-weekly intravenous dosing.

Efficacy

The efficacy of the clinical trial will be assessed by evaluating the primary and secondary endpoints. The primary efficacy endpoint is the rate of serious bacterial infections (SBIs), which include bacteraemia/sepsis, bacterial meningitis, osteomyelitis/septic arthritis, bacterial pneumonia, and visceral abscess, per person-year on treatment. This will be analyzed over a 52-week efficacy period. Additionally, the primary pharmacokinetic (PK) endpoint is the average total **immunoglobulin G (IgG)** concentration (Cav) on steady-state dosing.

Secondary endpoints include the annual rate of infections of any type or seriousness, time to resolution of infections, and the use of antibiotics, characterized by the number of days on antibiotics and the annual rate of treatment episodes. Hospitalizations due to infection, episodes of fever, and days lost from work, school, kindergarten, or daycare due to infection will also be measured. Quality of life (QoL) assessments will be conducted using the Child Health Questionnaire-Parent Form (CHQPF50) for patients under 14 years and the SF-36 Health Survey for patients aged 14 years and older.

Inclusion and Exclusion Criteria

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Inclusion Criteria

Age of ≥2 years and ≤75 years
Documented and confirmed diagnosis of PID as defined by European Society of Immunodeficiencies (ESID) and the Pan American Group for Immune Deficiency (PAGID) and requiring immunoglobulin replacement therapy due to hypogammaglobulinaemia or agammaglobulinaemia. The exact type of PID must be recorded.
At least 12 weeks of regular treatment before the screening visit (i.e., with a stable dosing interval) with any IVIG, SCIG, or fSCIG, with a stable IgG dose between 200 and 800 mg/kg/month. A stable dose is defined as one that deviates less than ±25% from the mean dose for all infusions within this 12-week period before screening.
Trough level of IgG ≥5 g/L at screening and documentation of an IgG trough level of ≥5 g/L at least once within the previous 12 weeks.
Freely given written informed consent from adult patients or freely given written informed consent from the patient’s parent(s)/legal guardian(s) and written informed assent from paediatric or adolescent patients in accordance with the applicable regulatory requirements, before any study-specific procedure takes place.
Willingness to comply with all aspects of the protocol, including blood sampling, for the duration of the study.

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Exclusion Criteria

Any acute infection requiring IV antibiotic treatment within 2 weeks before the screening visit or during the screening period, or any SBI within the 3 months prior to the screening visit or during the screening period.
The patient has isolated specific antibody deficiency disorder, isolated IgG subclass deficiency, or transient hypogammaglobulinaemia of infancy.
Current medical condition or history of condition known to cause secondary immune deficiency, for example, chronic lymphocytic leukaemia, lymphoma, multiple myeloma, or chronic or recurrent neutropenia (absolute neutrophil count <1000/µL).
Known history of ADRs to IgA contained in other products.
Body mass index >40 kg/m2.
Exposure to blood or any blood product or plasma derivative other than IgG for PID within 3 months before the first infusion of Newnorm.
History of or ongoing severe hypersensitivity, e.g., anaphylaxis or severe systemic response, or persistent reactions to blood or plasma-derived products, or to any component of Newnorm (such as glycine).
Severe liver dysfunction (alanine aminotransferase [ALT] >3 times the upper limit of normal for the expected normal range for the testing laboratory) at screening.
Known protein-losing enteropathies or proteinuria (known urinary protein loss of >1 g/24 h, or dipstick proteinuria of ≥3+).
Moderate to severe renal dysfunction (per investigator discretion based on estimated glomerular filtration rate [eGFR] ≤44 mL/min/1.73 m2, as defined by KDIGO Clinical Practice Guideline) or predisposition to acute renal failure (e.g., any degree of pre-existing renal dysfunction in presence of additional acute renal failure risk factors, e.g. routine treatment with known nephrotoxic drugs).
Uncontrolled diabetes mellitus (HbA1c > 7% / >53 mmol/mol).
Uncontrolled arterial hypertension (systolic blood pressure of ≥ 130 mmHg for the subject under 13 years of age, ≥ 140 mmHg for subject 13 to 17 years of age, and > 160 mmHg for adults).
Dysrhythmia/Tachycardia (resting heart rate > 100 bpm for adults/adolescents and > 120 bpm for children) and symptomatic bradycardia (resting heart rate < 60 bpm for adults, < 50 bpm for adolescents, and < 75 bpm for children in presence of symptoms e.g., low blood pressure, abnormal rhythm, chest discomfort, shortness of breath). Physiological sinus bradycardia in physically active adults/children/athletes is NOT an exclusion criterion).
The subject has a history of or current diagnosis of deep venous thrombosis or thromboembolism (e.g. myocardial infarction, cerebrovascular accident, or transient ischemic attack); history refers to an incident in the year prior to screening or 2 episodes over lifetime.
The subject is currently receiving anti-coagulation therapy which would make SC administration inadvisable (vitamin K antagonist, nonvitamin K antagonist oral anticoagulants [e.g. dabigatran etexilate targeting Factor IIa, rivaroxaban, edoxaban, and apixaban targeting Factor Xa], parenteral anticoagulants [e.g. fondaparinux]).
Treatment with oral or parenteral steroids either a.at daily doses >0.3 mg/kg of prednisone (or equivalent) within the last 12 weeks before screening or b. bolus treatment of a daily dose greater than 1 mg/kg of prednisone (or equivalent) for longer than 10 days within the last 12 weeks before screening. Courses of corticosteroids (intermittent) of not more than 10 days would not exclude a patient. Inhaled or topical corticosteroids are allowed.
Treatment with systemic immunosuppressants including chemotherapeutic agents 1 year before screening or immunomodulatory drugs 12 weeks before the screening visit.
Live viral vaccination (such as measles, rubella, mumps, or varicella) within 1 month before the first infusion of Newnorm, during the study period, and within 3 months after last infusion of Newnorm. Note: Seasonal inactivated (killed) influenza vaccines (incl. H1N1) are allowed. COVID vaccines (mRNA vaccine and a non-replicating viral vector vaccine) are allowed.
Treatment with any investigational medicinal product (IMP) within 3 months before the screening visit.
Presence of any condition likely to interfere with the evaluation of Newnorm or with the compliant conduct of the study.
Known or suspected abuse of alcohol, drugs, and/or psychotropic agents within 12 months before screening.
Known human immunodeficiency virus (HIV)-1/2, hepatitis B virus (HBV), or hepatitis C virus (HCV) infection or positive for HIV-1/2, HBV, or HCV at screening.
Women who are breast feeding, pregnant, or planning to become pregnant, or are unwilling to use an effective birth control method (refer to protocol Section 7.4.10.b) while on study and for 30 days following the last dose of study drug.
Men who are unwilling to use birth control to prevent pregnancy for the duration of the study (unless the female partner is using a hormonal contraception, IUD or IUS, or is postmenopausal).

Trial Status by Country

Country	Status	Start of Recruitment	Planned Patients
Germany	Not Recruiting	06 Jul 2021	10
Hungary	Not Recruiting	06 Jul 2021	10
Italy	Not Recruiting	06 Jul 2021	10
Poland	Not Recruiting	06 Jul 2021	10
Slovakia	Not Recruiting	06 Jul 2021	10