Primary Immune Deficiency Disorder
Conditions
Brief summary
Clinical phase 3 study to evaluate the efficacy, tolerability and safety of subcutaneous human immunoglobulin (octanorm) in patients with primary immunodeficiency diseases.
Detailed description
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
Interventions
BIOLOGICALOctanorm
Octanorm
Sponsors
Octapharma
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 70 Years
Healthy volunteers
No
Inclusion criteria
1. Age of ≥18 years and ≤70 years. 2. Confirmed diagnosis of PI requiring immunoglobulin replacement therapy due to hypogammaglobulinaemia or agammaglobulinaemia. The type of PI should be recorded. 3. 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). 4. 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. 5. 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 6. Patient must freely give written informed consent. 7. Willingness to comply with all aspects of the protocol, including blood sampling, for the duration of the study.
Exclusion criteria
1. Acute infection requiring intravenous (IV) antibiotic treatment within 2 weeks prior to and during the screening period. 2. Known history of adverse reactions to Immunoglobulin A in other products. 3. Patients with body mass index \>40 kg/m2 4. 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. 5. 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). 6. History of malignancies of lymphoid cells and immunodeficiency with lymphoma. 7. Severe liver function impairment (ALAT 3 times above upper limit of normal). 8. Known protein-losing enteropathies or proteinuria. 9. 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). 10. 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. 11. Patients with chronic obstructive pulmonary disease (COPD) stage Global Initiative for Chronic Obstructive Lung Disease (GOLD) III or IV. 12. Treatment with immunosuppressive drugs. 13. Live viral vaccination (such as measles, rubella, mumps and varicella) within the last 2 months prior to first infusion of octanorm. 14. Treatment with any IMP within 3 months prior to first infusion of octanorm. 15. Presence of any condition that is likely to interfere with the evaluation of study medication or satisfactory conduct of the trial. 16. Known or suspected to abuse alcohol, drugs, psychotropic agents or other chemicals within the past 12 months prior to first infusion of octanorm. 17. Known or suspected human immunodeficiency virus (HIV), hepatitis C virus (HCV), or hepatitis B virus (HBV) infection. 18. Pregnant or nursing women; planned pregnancy during course of the study
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Serious Bacterial Infections Per Person-Year on Treatment | Primary Treatment Period (24 Weeks) | Serious Bacterial Infections defined as bacteraemia/sepsis, bacterial meningitis, osteomyelitis/septic arthritis, bacterial pneumonia, and visceral abscess |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Patients With Other Infections | Primary Treatment Period (24 Weeks) | The number of patients with all infections of any kind or seriousness. |
| Number of Other Infections | Primary Treatment Period (24 Weeks) | 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. |
| Time to Resolution of Infections | Primary Treatment Period (24 Weeks) and Whole Treatment Period (up to 36 Weeks) | 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. |
| Number of Participants Using Antibiotics From 0 to > 20 Days | Primary Treatment Period (24 Weeks) | Number of patients using antibiotics during the whole treatment period (36 weeks) grouped per number of days with antibiotic usage. |
| Annual Rate of Antibiotic Use | Primary Treatment Period (24 Weeks) | 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 |
| Rate of Hospitalizations Due to Infection | Primary Treatment Period (24 Weeks) | Annual Rate of Hospitalizations due to Infection |
| Episodes of Fever | Primary Treatment Period (24 Weeks) and Whole Treatment Period (up to 36 Weeks) | Number of episodes of fever |
| Rate of Episodes of Fever | Primary Treatment Period (24 Weeks) | 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 |
| Hospitalizations Due to Infection | Primary Treatment Period (24 Weeks) | Number of days spent in hospital due to infection |
| Changes in the Subscales of the Form-36 Health Survey Scores From Baseline to the End of the Study | Baseline to the end of study (up to 36 weeks) | 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. |
| Trough Levels of Serum Total IgG | At baseline and at last infusion (week 33) | Total IgG trough concentrations were measured in serum samples taken before each infusion given at the study site. |
| Number of Participants Experiencing Treatment-Emergent AEs | Up to 36 weeks | TEAEs were classified as temporally associated if the onset was during the infusion or within 72 hours after the end of the infusion. |
| Proportion of Infusions With at Least 1 Temporally Associated AE | Up to 36 weeks | 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. |
| Total Number of Adverse Events Regardless of Causality | Up to 36 weeks | 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. |
| Number of Related Adverse Events | Up to 36 weeks | A related adverse event is an AE for which a causal relationship between the IMP and the AE cannot be ruled out. |
| Number of Infusions With Infusion Site Reaction | Up to 36 weeks | Total number of infusions that triggered an infusion site reaction and number of infusions that triggered mild, moderate, severe or no infusion site reactions. |
| Annual Rate of Infections | Up to 36 weeks | The annual rate of all infections of any kind of seriousness |
| Patients With Days Missed From Work/Study Due to Infections and Treatment | Primary Treatment Period (24 Weeks) | Total number of patients who missed days from work or study due to infections or treatment thereof. |
Countries
Russia
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| All Patients Full analysis set (FAS population) included all patients who received at least one administration of the study drug and for whom any post-baseline data was available | 25 |
| Total | 25 |
Baseline characteristics
| Characteristic | All Patients |
|---|---|
| Age, Continuous | 35.24 years |
| BMI (Body Mass Index) | 23.02 kg/m^2 STANDARD_DEVIATION 3.48 |
| Height | 170 centimeters STANDARD_DEVIATION 8.68 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 25 Participants |
| Region of Enrollment Russia | 25 participants |
| Sex: Female, Male Female | 15 Participants |
| Sex: Female, Male Male | 10 Participants |
| Weight | 66.49 kilograms STANDARD_DEVIATION 10.54 |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 0 / 25 |
| other Total, other adverse events | 18 / 25 |
| serious Total, serious adverse events | 0 / 25 |
Outcome results
Primary
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
Time frame: Primary Treatment Period (24 Weeks)
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Octanorm | Number of Serious Bacterial Infections Per Person-Year on Treatment | 0 SBI per patient year |
Secondary
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
Time frame: Primary Treatment Period (24 Weeks)
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Octanorm | Annual Rate of Antibiotic Use | 1.73 treatment episodes per person-year |
Secondary
Annual Rate of Infections
The annual rate of all infections of any kind of seriousness
Time frame: Up to 36 weeks
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Octanorm | Annual Rate of Infections | 2.37 infections/person-year |
Secondary
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.
Time frame: Baseline to the end of study (up to 36 weeks)
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Octanorm | Changes in the Subscales of the Form-36 Health Survey Scores From Baseline to the End of the Study | Physical Functioning | 2.5 score on a scale | Standard Deviation 12.25 |
| Octanorm | Changes in the Subscales of the Form-36 Health Survey Scores From Baseline to the End of the Study | Role Physical | 8.07 score on a scale | Standard Deviation 25.83 |
| Octanorm | Changes in the Subscales of the Form-36 Health Survey Scores From Baseline to the End of the Study | Bodily Pain | 21.38 score on a scale | Standard Deviation 28.12 |
| Octanorm | Changes in the Subscales of the Form-36 Health Survey Scores From Baseline to the End of the Study | General Health | -1.08 score on a scale | Standard Deviation 15.16 |
| Octanorm | Changes in the Subscales of the Form-36 Health Survey Scores From Baseline to the End of the Study | Vitality | 5.73 score on a scale | Standard Deviation 17.67 |
| Octanorm | Changes in the Subscales of the Form-36 Health Survey Scores From Baseline to the End of the Study | Social Functioning | 7.81 score on a scale | Standard Deviation 23.26 |
| Octanorm | Changes in the Subscales of the Form-36 Health Survey Scores From Baseline to the End of the Study | Role Emotional | 10.76 score on a scale | Standard Deviation 22.18 |
| Octanorm | Changes in the Subscales of the Form-36 Health Survey Scores From Baseline to the End of the Study | Mental Health | 5.83 score on a scale | Standard Deviation 20.62 |
Secondary
Episodes of Fever
Number of episodes of fever
Time frame: Primary Treatment Period (24 Weeks) and Whole Treatment Period (up to 36 Weeks)
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Octanorm | Episodes of Fever | Primary Treatment Period | 6 episodes of fever |
| Octanorm | Episodes of Fever | Whole Treatment Period | 8 episodes of fever |
Secondary
Hospitalizations Due to Infection
Number of days spent in hospital due to infection
Time frame: Primary Treatment Period (24 Weeks)
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Octanorm | Hospitalizations Due to Infection | 0 days | Standard Deviation 0 |
Secondary
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.
Time frame: Up to 36 weeks
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Octanorm | Number of Infusions With Infusion Site Reaction | Infusions with Mild Local Site Reactions | 102 infusions |
| Octanorm | Number of Infusions With Infusion Site Reaction | Infusions with Moderate Local Site Reactions | 17 infusions |
| Octanorm | Number of Infusions With Infusion Site Reaction | Infusions with Severe Local Site Reactions | 0 infusions |
| Octanorm | Number of Infusions With Infusion Site Reaction | Infusions with No Infusion Site Reaction | 659 infusions |
Secondary
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.
Time frame: Primary Treatment Period (24 Weeks)
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Octanorm | Number of Other Infections | Number of Severe Infections | 0 Infections |
| Octanorm | Number of Other Infections | Number of Mild Infections | 17 Infections |
| Octanorm | Number of Other Infections | Number of Moderate Infections | 9 Infections |
Secondary
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.
Time frame: Up to 36 weeks
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Octanorm | Number of Participants Experiencing Treatment-Emergent AEs | Without Infusion Site Reactions and With Infection | 18 patients |
| Octanorm | Number of Participants Experiencing Treatment-Emergent AEs | Without Infusion Site Reactions/Without Infection | 11 patients |
| Octanorm | Number of Participants Experiencing Treatment-Emergent AEs | Infections (only) | 16 patients |
Secondary
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.
Time frame: Primary Treatment Period (24 Weeks)
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Octanorm | Number of Participants Using Antibiotics From 0 to > 20 Days | Patients with 8 Treatment Days | 2 Participants |
| Octanorm | Number of Participants Using Antibiotics From 0 to > 20 Days | Patients with >20 Treatment Days | 5 Participants |
| Octanorm | Number of Participants Using Antibiotics From 0 to > 20 Days | Patients with 0 Treatment Days | 14 Participants |
| Octanorm | Number of Participants Using Antibiotics From 0 to > 20 Days | Patients with 5 Treatment Days | 2 Participants |
| Octanorm | Number of Participants Using Antibiotics From 0 to > 20 Days | Patients with 7 Treatment Days | 1 Participants |
Secondary
Number of Patients With Other Infections
The number of patients with all infections of any kind or seriousness.
Time frame: Primary Treatment Period (24 Weeks)
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Octanorm | Number of Patients With Other Infections | Number of Patients With Infections | 14 Participants |
| Octanorm | Number of Patients With Other Infections | Number of Patients with 0 Infections | 10 Participants |
| Octanorm | Number of Patients With Other Infections | Number of Patients with 1 Infection | 9 Participants |
| Octanorm | Number of Patients With Other Infections | Number of Patients with 2 Infections | 2 Participants |
| Octanorm | Number of Patients With Other Infections | Number of Patients with 3 Infections | 0 Participants |
| Octanorm | Number of Patients With Other Infections | Number of Patients with 4 Infections | 2 Participants |
| Octanorm | Number of Patients With Other Infections | Number of Patients with 5 Infections | 1 Participants |
Secondary
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.
Time frame: Up to 36 weeks
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Octanorm | Number of Related Adverse Events | 3 related adverse events |
Secondary
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.
Time frame: Primary Treatment Period (24 Weeks)
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Octanorm | Patients With Days Missed From Work/Study Due to Infections and Treatment | 3 Participants |
Secondary
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.
Time frame: Up to 36 weeks
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Octanorm | Proportion of Infusions With at Least 1 Temporally Associated AE | .013 proportion of infusions |
Secondary
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
Time frame: Primary Treatment Period (24 Weeks)
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Octanorm | Rate of Episodes of Fever | 0.55 episodes of fever per person-year |
Secondary
Rate of Hospitalizations Due to Infection
Annual Rate of Hospitalizations due to Infection
Time frame: Primary Treatment Period (24 Weeks)
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Octanorm | Rate of Hospitalizations Due to Infection | 0 hospitalizations/person-year |
Secondary
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.
Time frame: Primary Treatment Period (24 Weeks) and Whole Treatment Period (up to 36 Weeks)
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Octanorm | Time to Resolution of Infections | Whole Treatment Period | 10.32 days |
| Octanorm | Time to Resolution of Infections | Primary Treatment Period | 9.53 days |
Secondary
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.
Time frame: Up to 36 weeks
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Octanorm | Total Number of Adverse Events Regardless of Causality | 59 adverse events |
Secondary
Trough Levels of Serum Total IgG
Total IgG trough concentrations were measured in serum samples taken before each infusion given at the study site.
Time frame: At baseline and at last infusion (week 33)
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Octanorm | Trough Levels of Serum Total IgG | Screening Draw 1 | 8.71 g/L | Standard Deviation 2.68 |
| Octanorm | Trough Levels of Serum Total IgG | Week 33 | 9.99 g/L | Standard Deviation 1.79 |