| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Primary Immunodeficiency Diseases |
|
| E.1.1.1 | Medical condition in easily understood language |
| Congenital diseases resulting in low immunoglobulin levels in the blood |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Immune System Diseases [C20] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 14.1 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10064859 |
| E.1.2 | Term | Primary immunodeficiency syndrome |
| E.1.2 | System Organ Class | 10010331 - Congenital, familial and genetic disorders |
|
| E.1.3 | Condition being studied is a rare disease | Yes |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| The primary objective of this study is to evaluate the efficacy of Immune Globulin Subcutaneous (Human) (IGSC), 20% in subjects with PID. |
|
| E.2.2 | Secondary objectives of the trial |
The secondary objectives of this study, in addition to further efficacy assessments, are to evaluate the safety, tolerability, and pharmacokinetic (PK) characteristics of Immune Globulin Subcutaneous (Human) (IGSC), 20% in subjects with PID.
Exploratory Objective(s)
Exploratory objectives are to assess dose adjustments, quality of life aspects, treatment satisfaction and treatment preference. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Subjects who meet ALL of the following criteria are eligible for this study:
1. Subject must have a documented diagnosis of a form of primary humoral immunodeficiency involving antibody formation and requiring gammaglobulin replacement, as defined according to the IUIS Scientific Committee 2009 and by diagnostic criteria according to Conley et al. (1999). The diagnosis must be confirmed by the Medical Director prior to first treatment with IP in the study.
2. Subject is 2 years or older at the time of screening.
3. Written informed consent is obtained from either the subject or the subject’s legally authorized representative prior to any study-related procedures and study product administration.
4. Subject has been receiving a consistent monthly equivalent dose of IgG over a period of at least 3 months prior to first treatment with IP at an average minimum dose over that interval equivalent to 300 mg/kg bodyweight (BW)/4 weeks and a maximum dose equivalent to 1.0 gram/kg BW/4 weeks.
Examples of pre-study dosing frequency:
a) IV at mean intervals of approximately 3 or 4 weeks or
b) SC at mean intervals of approximately 1 or 2 weeks
c) SC alternative treatment schedule (e.g. 2x/week)
5. Subject has a serum trough level of IgG >5 g/L at screening
6. Subject has not had a serious bacterial infection within the 3 months prior to screening.
7. Subject is willing and able to comply with the requirements of the protocol. |
|
| E.4 | Principal exclusion criteria |
Subjects who meet ANY of the following criteria are not eligible for this study:
1. Subject has a known history of or is positive at screening for one or more of the following:
hepatitis B surface antigen (HBsAg), polymerase chain reaction (PCR) for hepatitis C virus (HCV), PCR for human immunodeficiency virus (HIV) Type 1/2.
2. Abnormal laboratory values at screening meeting any one of the following criteria (abnormal tests may be repeated once to determine if they are persistent):
a) Persistent alanine aminotransferase (ALT) and aspartate amino transferase (AST) >2.5 times the upper limit of normal for the testing laboratory
b) Persistent severe neutropenia (defined as an absolute neutrophil count [ANC] ≤500/[mm]3)
3. Subject has creatinine clearance (CLcr) value that is <60% of normal for age and gender.
4. Subject has been diagnosed with or has a malignancy (other than adequately treated basal cell or squamous cell carcinoma of the skin or carcinoma in situ of the cervix), unless the disease-free period prior to screening exceeds 5 years.
5. Subject is receiving anti-coagulation therapy or has a history of thrombotic episodes (including deep vein thrombosis, myocardial infarction, cerebrovascular accident, pulmonary embolism) within 12 months prior to screening or a history of thrombophilia.
6. Subject has abnormal protein loss (protein losing enteropathy, nephrotic syndrome).
7. Subject has anemia that would preclude phlebotomy for laboratory studies, according to standard practice at the site.
8. Subject has an ongoing history of hypersensitivity or persistent reactions (urticaria, breathing difficulty, severe hypotension, or anaphylaxis) following IV immunoglobulin, SC immunoglobulin, and/or Immune Serum Globulin (ISG) infusions.
9. Subject has severe immunoglobulin A (IgA) deficiency (IgA less than 0.07g/L) with known anti IgA antibodies and a history of hypersensitivity.
10. Subject is on preventative (prophylactic) systemic antibacterial antibiotics at doses sufficient to treat or prevent bacterial infections, and cannot stop these antibiotics at the time of screening.
11. Subject has active infection and is receiving antibiotic therapy for the treatment of infection at the time of screening.
12. Subject has a bleeding disorder or a platelet count less than 20,000/μL, or who, in the opinion of the investigator, would be at significant risk of increased bleeding or bruising as a result of SC therapy.
13. Subject has total protein >9 g/dL or myeloma, or macroglobulinemia (IgM) or paraproteinemia.
14. Women of childbearing potential meeting any one of the following criteria
a) subject presents with a positive pregnancy test
b) subject is breast feeding
c) subject intends to begin nursing during the course of the study
d) subject does not agree to employ adequate birth-control measures (e.g. intrauterine device, diaphragm or condom [for male partner] with spermicidal jelly or foam, or birth control pills/patches) throughout the course of the study.
15. Subject has participated in another clinical study and has been exposed to an investigational product (IP) or device within 30 days prior to study enrollment (exception: treatment with immunoglobulin pre-study).
16. Subject is scheduled to participate in another (non-Baxter) non-observational (interventional) clinical study involving an IP or device during the course of the study.
17. Severe dermatitis that would preclude adequate sites for safe product administration. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| The primary endpoint is the acute serious bacterial infection rate defined as the mean number of acute serious bacterial infections per subject per year in the intent-to-treat population. Acute serious bacterial infections will include bacteremia / sepsis, bacterial meningitis, osteomyelitis / septic arthritis, bacterial pneumonia, and visceral abscess, diagnosed according to the Diagnostic Criteria for Serious Acute Bacterial Infections of the US Food and Drug Administration, Center for Biologics Evaluation and Research; Guidance for Industry - Safety, Efficacy, and Pharmacokinetic Studies to Support Marketing of Immune Globulin Intravenous (Human) as Replacement Therapy for Primary Humoral Immunodeficiency, June 2008. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| Infections will be reported as adverse events throughout the study and the number and types of infections will be determined. |
|
| E.5.2 | Secondary end point(s) |
EFFICACY
a. Trough levels
i. Immunoglobulin G (IgG) trough levels during approximately 3 months treatment with SUBCUVIA (subcutaneously) or KIOVIG (intravenously) (Study Epoch 1) and IgG trough levels after SC administration of IGSC, 20% (Study Epoch 2).
ii. Trough levels of specific antibodies to clinically relevant pathogens (Clostridium tetani toxoid, Haemophilus influenzae and Hepatitis B Virus) during approximately 3 months treatment with SUBCUVIA (subcutaneously) or KIOVIG (intravenously) (Study Epoch 1) and trough levels of these specific antibodies after SC administration of IGSC, 20% (Study Epoch 2)
b. Other PK parameters
The following PK parameters will also be assessed for IgG: area under the curve (AUC), clearance (CL) for IV and apparent clearance (Cl/F) for SC administration, maximum concentration (Cmax), minimum concentration (Cmin), and time to maximum concentration (Tmax).
2. Infections
a. The annual rate of all infections per subject
b. The annual rate of sinus infections per subject
c. The annual rate of fever episodes per subject
d. Days not able to attend school/work or to perform normal daily activities due to illness/infection
e. Days on antibiotics
f. Number of hospitalizations and length of stay (in days)
g. Acute (urgent or unscheduled) physician visits due to illness/infection
Safety:
1. Related AEs
a. Number of AEs (including and excluding infections) determined by the investigator to be related to the study drug that occur at any time during the study ("related") divided by the number of subjects
b. Number of AEs (including and excluding infections) determined by the investigator to be related to the study drug that occur at any time during the study ("related") divided by the number of infusions
2. All AEs
a. Annual rate of serious adverse events (SAEs), related and not related
b. Rates of AEs (including and excluding infections) defined as number of AEs categorized by Medical Dictionary for Regulatory Activities (MedDRA) preferred terms, seriousness, and severity, divided by the number of subjects c. Rates of AEs (including and excluding infections) defined as number of AEs categorized by MedDRA preferred terms, seriousness, and severity, divided by the number of infusions
3. Local AEs
a. Proportion of infusions in Study Epoch 1 and in Study Epoch 2 associated with one or more local AEs (including and excluding infections), at any time during the study
b. Proportion of subjects in Study Epoch 1 and in Study Epoch 2 reporting one or more local AEs
4. Temporally associated AEs
a. Number of AEs (including and excluding infections) that begin during the infusion or within 72 hours of completion of infusion divided by the number of subjects
b. Number of AEs (including and excluding infections) that begin during or within 72 hours of
completion of infusion divided by the number of infusions
5. Short term tolerance
a. Blood pressure
b. Heart rate (pulse)
c. Respiratory rate
d. Body temperature
e. Proportion of infusions for which the infusion rate was reduced and/or the infusion interrupted or stopped for tolerability concerns or for AEs
f. Proportion of subjects for whom the infusion rate was reduced and/or the infusion interrupted or stopped for tolerability concerns or for AEs
g. Proportion of infusions tolerated with intravenous (IV) or subcutaneous (SC) administration
6. Hemolysis evaluation
Occurrences of hemolysis at any time during the study |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
IgG Trough Levels:
• Baseline
• Study Epoch 1
- IV treatment: At each infusion (every 3 weeks or every 4 weeks)
- SC treatment: Every 4 weeks (at the mandatory site infusion visit)
• Study Epoch 2:
- at infusion numbers 1, 5, and 13,
- then weekly at infusion numbers 21, 22, 23, 24, 25, 26 and 27,
- then every 8 weeks at infusion numbers 35, 43 and 51.
• End-of-Study Visit
Infections
Throughout the study
Safety Endpoints:
Throughout the study
Hemolysis Tests:
- Screening visit
- Once during IV and SC treatment in Epoch 1 (at the PK assessment infusion).
- SC treatment Epcoch 2: At infusions 1, 2, 21, 22 and 52 |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | No |
| E.8.1.1 | Randomised | No |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 4 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 18 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | No |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.7 | Trial has a data monitoring committee | No |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
| Last visit of the last subject. |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 2 |
| E.8.9.1 | In the Member State concerned months | 3 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 2 |
| E.8.9.2 | In all countries concerned by the trial months | 6 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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