Study to Evaluate the Efficacy, Tolerability and Safety of Octanorm in Patients With Primary Immunodeficiency Diseases

Study Overview
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Brief Summary
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Clinical phase 3 study to evaluate the efficacy, tolerability and safety of subcutaneous human immunoglobulin (octanorm) in patients with primary immunodeficiency diseases.

Detailed Description
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Octanorm (cutaquig®) is a 16.5% human normal immunoglobulin solution developed by Octapharma for subcutaneous administration (SCIG). It is supplied as a liquid formulation ready to use. One important therapeutic use of immunoglobulins is to provide antibodies to prevent viral and bacterial diseases (replacement therapy). Children and adults with a Primary Immunodeficiency Disease (PID) have an increased risk of recurrent bacterial and viral infections. These diseases can be severe and can lead to substantial morbidity. Responses to antibacterial therapy are often poor. At present, most primary immune deficiencies are not curable, but SCIGs have been shown to decrease the total number of severe infections and the duration of hospitalization. This study evaluated the efficacy, safety and tolerability of octanorm in adult PID patients in an open-label, multi center, phase 3 study with an 8-week wash-in/wash-out period followed by a 6-month efficacy period

Official Title
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Clinical Phase 3 Study to Evaluate the Efficacy, Tolerability and Safety of Subcutaneous Human Immunoglobulin (Octanorm) in Patients With Primary Immunodeficiency Diseases.

Conditions
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Primary Immune Deficiency Disorder

Intervention / Treatment
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* Biological: Octanorm


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age of ≥18 years and ≤70 years. Confirmed diagnosis of PI requiring immunoglobulin replacement therapy due to hypogammaglobulinaemia or agammaglobulinaemia. The type of PI should be recorded. Patients with at least 4 infusions on regular treatment with any Intravenous Immunoglobulin (IVIG) prior to entering the study. Constant IVIG dose between 200 and 800 mg/kg body weight (the individual doses of the last 4 infusions should not vary by more than ±25% of the mean dose for the last 4 infusions). Availability of at least 2 IgG trough levels with an IgG level of ≥5.0 g/L from the period of the last 4 IVIG infusions. Negative result on a pregnancy test (Human Chorionic Gonadotrophin [HCG]-based assay in urine) for women of childbearing potential and use of a reliable method of contraception for the duration of the study. Women of non-childbearing potential must be post-menopausal (amenorrhoeic for at least 12 months) or surgically sterile. Examples for medically acceptable methods of birth control for this study include: Oral, implantable, transdermal or injectable contraceptives Intrauterine device Condoms; diaphragm or vaginal ring with spermicidal jellies or cream Sexual abstinence Vasectomised partner Patient must freely give written informed consent. Willingness to comply with all aspects of the protocol, including blood sampling, for the duration of the study. Exclusion Criteria: Acute infection requiring intravenous (IV) antibiotic treatment within 2 weeks prior to and during the screening period. Known history of adverse reactions to Immunoglobulin A in other products. Patients with body mass index >40 kg/m2 Exposure to blood or any blood product or plasma derivatives, other than IVIG treatment of PI, within the past 3 months prior to first infusion of octanorm. Ongoing history of hypersensitivity or persistent reactions to blood or plasma derived products, or any component of the investigational medicinal product (IMP) (such as Polysorbate 80). History of malignancies of lymphoid cells and immunodeficiency with lymphoma. Severe liver function impairment (ALAT 3 times above upper limit of normal). Known protein-losing enteropathies or proteinuria. Presence of renal function impairment (creatinine >120 µM/L or creatinine >1.35 mg/dL), or predisposition for acute renal failure (e.g., any degree of pre-existing renal insufficiency or routine treatment with known nephritic drugs). Treatment with enteral or parenteral steroids for ≥30 days or when given intermittently or as bolus, at daily doses ≥0.15 mg/kg. Inhaled corticosteroids are allowed. Patients with chronic obstructive pulmonary disease (COPD) stage Global Initiative for Chronic Obstructive Lung Disease (GOLD) III or IV. Treatment with immunosuppressive drugs. Live viral vaccination (such as measles, rubella, mumps and varicella) within the last 2 months prior to first infusion of octanorm. Treatment with any IMP within 3 months prior to first infusion of octanorm. Presence of any condition that is likely to interfere with the evaluation of study medication or satisfactory conduct of the trial. Known or suspected to abuse alcohol, drugs, psychotropic agents or other chemicals within the past 12 months prior to first infusion of octanorm. Known or suspected human immunodeficiency virus (HIV), hepatitis C virus (HCV), or hepatitis B virus (HBV) infection. Pregnant or nursing women; planned pregnancy during course of the study

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 70 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Octanorm<br>Human Normal Immunoglobulin for Subcutaneous Administration (Octanorm) is a liquid formulation of normal human IgG at a concentration of 16.5% administered as a SC infusion at weekly intervals (either done at the study center [during first training sessions and then for every 4th administration] or at home by the patient or caregiver). The initial weekly dose was determined based on subjects' previous IVIG treatment. | Biological: Octanorm<br>* Octanorm<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Serious Bacterial Infections Per Person-Year on Treatment | Serious Bacterial Infections defined as bacteraemia/sepsis, bacterial meningitis, osteomyelitis/septic arthritis, bacterial pneumonia, and visceral abscess | Primary Treatment Period (24 Weeks) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Patients With Other Infections | The number of patients with all infections of any kind or seriousness. | Primary Treatment Period (24 Weeks) | 
| Number of Other Infections | For other infections, the Medical Dictionary for Regulatory Activities (MedDRA) preferred term was used to determine the type of infection. They were grouped into the following categories as determined by a medical expert: Ear infections, eye infections, infections of the gastrointestinal tract, infections of the genitourinary tract, upper respiratory tract infections, lower respiratory tract infections, infections of the skin, and infections not elsewhere classified. | Primary Treatment Period (24 Weeks) | 
| Time to Resolution of Infections | Since infections were reported as adverse events, the time to resolution of an infection was the time from the start date of the infection adverse event to the end date of the infection adverse event. | Primary Treatment Period (24 Weeks) and Whole Treatment Period (up to 36 Weeks) | 
| Number of Participants Using Antibiotics From 0 to > 20 Days | Number of patients using antibiotics during the whole treatment period (36 weeks) grouped per number of days with antibiotic usage. | Primary Treatment Period (24 Weeks) | 
| Annual Rate of Antibiotic Use | The number of antibiotic treatment episodes per person-year of treatment was calculated by the following formula: Total number of antibiotic treatment episodes / patient-years of Octanorm treatment | Primary Treatment Period (24 Weeks) | 
| Hospitalizations Due to Infection | Number of days spent in hospital due to infection | Primary Treatment Period (24 Weeks) | 
| Rate of Hospitalizations Due to Infection | Annual Rate of Hospitalizations due to Infection | Primary Treatment Period (24 Weeks) | 
| Episodes of Fever | Number of episodes of fever | Primary Treatment Period (24 Weeks) and Whole Treatment Period (up to 36 Weeks) | 
| Rate of Episodes of Fever | The number of episodes of fever per person-year of treatment was calculated by the following formula: Total number of episodes of fever / patient-years of Octanorm treatment | Primary Treatment Period (24 Weeks) | 
| Patients With Days Missed From Work/Study Due to Infections and Treatment | Total number of patients who missed days from work or study due to infections or treatment thereof. | Primary Treatment Period (24 Weeks) | 
| Changes in the Subscales of the Form-36 Health Survey Scores From Baseline to the End of the Study | The SF-36-HS consists of 36 items organized into 8 subscales. The 8 subscales could be combined into 2 summary scores, physical and mental. The calculated summary scores were transformed to a range of 0-100, where a higher score indicates better health. A positive change score indicates improvement. | Baseline to the end of study (up to 36 weeks) | 
| Trough Levels of Serum Total IgG | Total IgG trough concentrations were measured in serum samples taken before each infusion given at the study site. | At baseline and at last infusion (week 33) | 
| Number of Participants Experiencing Treatment-Emergent AEs | TEAEs were classified as temporally associated if the onset was during the infusion or within 72 hours after the end of the infusion. | Up to 36 weeks | 
| Proportion of Infusions With at Least 1 Temporally Associated AE | The proportion of infusions with at least 1 temporally associated AE (TAAE) was calculated by dividing the total number of TAAE by the total number of infusions. | Up to 36 weeks | 
| Total Number of Adverse Events Regardless of Causality | An AE is any untoward medical occurrence in a study patient receiving an IMP and which does not necessarily have a causal relationship with this treatment. | Up to 36 weeks | 
| Number of Related Adverse Events | A related adverse event is an AE for which a causal relationship between the IMP and the AE cannot be ruled out. | Up to 36 weeks | 
| Number of Infusions With Infusion Site Reaction | Total number of infusions that triggered an infusion site reaction and number of infusions that triggered mild, moderate, severe or no infusion site reactions. | Up to 36 weeks | 
| Annual Rate of Infections | The annual rate of all infections of any kind of seriousness | Up to 36 weeks |