Primary Immunodeficiency
Conditions
Brief summary
Phase 3 multicenter, open-label study of safety, tolerability, efficacy, and pharmacokinetics (PK) of ProMetic's Immune Globulin Intravenous (Human) 10%, the investigational medicinal product \[IMP\]), in Adults and Children with Primary Immunodeficiency Diseases (PIDD).
Detailed description
This is a pivotal Phase 3, open-label, single-arm, multicenter study to assess the tolerability, safety, efficacy, and Pharmacokinetics of the Investigational Medicinal Product in adults and children with Primary Immunodeficiency Diseases (PIDD). A total of approximately 75 subjects aged 2-80 years will be enrolled in the study. Subjects who switch from an investigational immune globulin or subcutaneous immune globulin (IGSC) are required to receive a stable dose of commercial product (CP), which is a licensed commercially available immune globulin intravenous (IGIV) product for at least 3 cycles before they can be given the Investigational Medicinal Product . This study schema will result in the Commercial Product Treatment Period and Investigational Medicinal Product Treatment Period. All subjects will be treated on an outpatient basis with the Investigational Medicinal Product for approximately 1 year, with the dose and schedule based on their previous IGIV treatment regimen (21-day or 28-day dosing interval). A subset of subjects will participate in a Pharmacokinetics sub-study. The primary objective of the study is to examine the rate of clinically documented serious bacterial infections (SBIs) in subjects treated with the Investigational Medicinal Product to achieve a rate of less than one SBI per year.
Interventions
BIOLOGICALImmune Globulin Intravenous
Gammargard, Gammaplex,Gamunex, or Octogam IGIV Product
BIOLOGICALPrometic's Immune Globulin Intravenous 10%
Liquid formulation of Prometic Immune Globulin Intravenous 10% (human) in 50 mL vials containing 100 mg/mL of immunoglobulin G (IgG)
Sponsors
Atlantic Research Group
Prometic Biotherapeutics, Inc.
Study design
Allocation
NON_RANDOMIZED
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
2 Years to 80 Years
Healthy volunteers
No
Inclusion criteria
1. Subject is male or female between the ages of 2 and 80 years at Screening. 2. Female subjects of childbearing potential must agree to employ adequate birth control measures, as determined by their IRB/IEC, for the duration of the study. 3. The subject must have one of the following three diagnoses (isolated PIDD of other types will be excluded): * Common variable immunodeficiency * X-linked agammaglobulinemia * Hyper-IgM syndrome and documented low IgG levels (\<4.5 mg/mL \[450 mg/dL\]). 4. Subjects must have been treated with a stable dose of immune globulin administered intravenously (IGIV) or subcutaneously (IGSC) and has documented trough or steady state IgG levels of ≥ 5 mg/mL.
Exclusion criteria
1. Subject has secondary immunodeficiency or has been diagnosed with dysgammaglobulinemia or isolated IgG subclass deficiency; has known hypoalbuminemia (\<3 gm/dL), protein-losing enteropathy, or nephrotic syndrome. 2. Subject has ever had a history of severe anaphylactic or anaphylactoid reaction to immunoglobulins or other blood products. 3. Subject has a known history of immunoglobulin A (IgA) deficiency and known anti-IgA antibodies, thrombotic event, such as deep vein thrombosis, myocardial infarction, cerebrovascular accident, pulmonary embolism, at any time. 4. Subject has received blood products except IGIV, IGSC, or albumin within the previous 12 months or has participated in another study (except for IGIV, IGSC studies) within the previous 4 weeks. 5. Subject has had cancer in the past 5 years, except for basal cell or squamous cell cancers of the skin. 6. Subject has had a documented active infection within 7 days prior to Screening, or subject is on continuous prophylactic antibiotics. 7. Subject is positive for human immunodeficiency virus (HIV)-1 or HIV-2, a positive hepatitis C virus (HCV) or hepatitis B virus (HBV). 8. Subject has levels of alanine aminotransferase (ALT) or aspartate aminotransferase (AST) \>2.5 times the upper limit of normal (ULN). 9. Subject has serum creatinine \>1.5 times the ULN or a severe chronic condition such as renal failure with proteinuria. 10. Subject has anemia with a hemoglobin level ≤8 g/dL. 11. Subject has severe neutropenia with neutrophil count ≤1000 per mmᴧ3 or has lymphopenia with \<500 per/ mmᴧ3. 12. Subject is taking prednisone at a dose ≥0.15 mg/kg/day and receiving other immunosuppressive drugs or chemotherapy. 13. Subject has known atrial fibrillation requiring anticoagulant therapy; congestive heart failure (New York Heart Association Class III/IV); cardiomyopathy; or cardiac arrhythmia associated with thromboembolic events, unstable or advanced ischemic heart disease, or hyperviscosity. 14. Subject has known decreased Protein C and/or Protein S levels. 15. Subject is positive for antibodies to β2GPI and/or β2GPI DI at Screening. 16. Female subject who is pregnant, breast-feeding, or planning a pregnancy during the course of the study. 17. A history of epilepsy or multiple episodes of migraine (defined as at least one episode within 6 months of enrolment) not completely controlled by medication, or any condition that is likely to interfere with evaluation of the IMP or satisfactory conduct of the study in the Investigator's opinion.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Annual Rate of Occurrence of Serious Bacterial Infections (SBI) | One year | SBIs were calculated for each subject as 52n/w, where n is the number of reported SBIs and w is the number of weeks on study. For the combined cohorts only, a 99% one-sided (upper) confidence limit for the incidence rate of SBIs (scaled to represent 12 months exposure if necessary) was derived, and the objective of demonstrating that the true infection rate was below 1 per subject per year was considered established if this upper limit was less than 1. To calculate the confidence limit, a negative binomial regression model will be used. This model includes an overdispersion parameter to account for possible intra-subject correlation as well as the actual time period each subject is on the study as an offset variable. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Trough Levels of IgG (Total) Prior to Each Prometic IGIV 10% Infusion | One year | Subject's total IgG levels will be assessed prior to each Prometic IGIV 10% infusion |
Countries
United States
Participant flow
Pre-assignment details
The term Participants for the overall study period reflects the number of subjects included in the analysis of the Prometic IGIV 10% Treatment period (75 subjects).
Participants by arm
| Arm | Count |
|---|---|
| Cohort 1 - Adult The Prometic IGIV 10% Treatment Period was the elapsed time from the first administration of Prometic IGIV 10% to study completion. Cohort 1 consisted of adult subjects aged 17-80 years. | 50 |
| Cohort 2 - Pediatric The Prometic IGIV 10% Treatment Period was the elapsed time from the first administration of Prometic IGIV 10% to study completion. Cohort 2 consisted of pediatric subjects aged 2 to \< 17 years. | 25 |
| Total | 75 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Lost to Follow-up | 1 | 0 |
| Overall Study | Major protocol violation | 0 | 1 |
| Overall Study | Other | 2 | 2 |
| Overall Study | Physician Decision | 0 | 1 |
| Overall Study | Withdrawal by Subject | 0 | 3 |
Baseline characteristics
| Characteristic | Total | Cohort 1 - Adult | Cohort 2 - Pediatric |
|---|---|---|---|
| Age, Continuous | 42.0 years | 57 years | 9 years |
| Ethnicity (NIH/OMB) Hispanic or Latino | 10 Participants | 4 Participants | 6 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 64 Participants | 45 Participants | 19 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 1 Participants | 1 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 1 Participants | 1 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 1 Participants | 1 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 3 Participants | 2 Participants | 1 Participants |
| Race (NIH/OMB) White | 70 Participants | 46 Participants | 24 Participants |
| Sex: Female, Male Female | 36 Participants | 31 Participants | 5 Participants |
| Sex: Female, Male Male | 39 Participants | 19 Participants | 20 Participants |
| Time since first Primary Immune Deficiency Disease (PIDD) diagnosis (years) | 6.4 years | 12 years | 1.9 years |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 66 | 0 / 75 |
| other Total, other adverse events | 57 / 66 | 72 / 75 |
| serious Total, serious adverse events | 5 / 66 | 7 / 75 |
Outcome results
Primary
Annual Rate of Occurrence of Serious Bacterial Infections (SBI)
SBIs were calculated for each subject as 52n/w, where n is the number of reported SBIs and w is the number of weeks on study. For the combined cohorts only, a 99% one-sided (upper) confidence limit for the incidence rate of SBIs (scaled to represent 12 months exposure if necessary) was derived, and the objective of demonstrating that the true infection rate was below 1 per subject per year was considered established if this upper limit was less than 1. To calculate the confidence limit, a negative binomial regression model will be used. This model includes an overdispersion parameter to account for possible intra-subject correlation as well as the actual time period each subject is on the study as an offset variable.
Time frame: One year
Population: CP Treatment Period and Prometic IGIV 10% Treatment Period: Analysis was performed on the all treated population, which consisted of all subjects who are enrolled into the study and received study treatment (CP or Prometic IGIV 10%) Prometic IGIV 10% Treatment Period Cohort 1 and Cohort 2: Analysis was performed on the all treated population, which consisted of all subjects who are enrolled into the study and received study treatment
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| CP Treatment Period | Annual Rate of Occurrence of Serious Bacterial Infections (SBI) | 0 Rate of events per subject per year |
| Prometic IGIV 10% Treatment Period | Annual Rate of Occurrence of Serious Bacterial Infections (SBI) | 0.01 Rate of events per subject per year |
| Prometic IGIV 10% Treatment Period (Cohort 1) | Annual Rate of Occurrence of Serious Bacterial Infections (SBI) | 0 Rate of events per subject per year |
| Prometic IGIV 10% Treatment Period (Cohort 2) | Annual Rate of Occurrence of Serious Bacterial Infections (SBI) | 0.03 Rate of events per subject per year |
Secondary
Trough Levels of IgG (Total) Prior to Each Prometic IGIV 10% Infusion
Subject's total IgG levels will be assessed prior to each Prometic IGIV 10% infusion
Time frame: One year
Population: CP Treatment Period and Prometic IGIV 10% Treatment Period: Analysis was performed on the all treated population, which consisted of all subjects who are enrolled into the study and received study treatment (CP or Prometic IGIV 10%) Prometic IGIV 10% Treatment Period Cohort 1 and Cohort 2: Analysis was performed on the all treated population, which consisted of all subjects who are enrolled into the study and received study treatment
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| CP Treatment Period | Trough Levels of IgG (Total) Prior to Each Prometic IGIV 10% Infusion | 1075.131 mg/dL | Standard Deviation 210.7547 |
| Prometic IGIV 10% Treatment Period | Trough Levels of IgG (Total) Prior to Each Prometic IGIV 10% Infusion | 1043.401 mg/dL | Standard Deviation 208.3044 |
| Prometic IGIV 10% Treatment Period (Cohort 1) | Trough Levels of IgG (Total) Prior to Each Prometic IGIV 10% Infusion | 1070.725 mg/dL | Standard Deviation 219.3308 |
| Prometic IGIV 10% Treatment Period (Cohort 2) | Trough Levels of IgG (Total) Prior to Each Prometic IGIV 10% Infusion | 988.752 mg/dL | Standard Deviation 175.7991 |