A Multi-Centre, Open-Label, Single Arm Trial to Evaluate Efficacy, Pharmacokinetics, and Safety and Tolerability of IGSC 20% in Subjects with Primary Immunodeficiency

• Register: EUCTR
• Last refreshed on: 20 July 2020
• Main ID: EUCTR2015-003290-15-GB
• Date of registration: 13/01/2016
• Prospective Registration: Yes
• Primary sponsor: Grifols Therapeutics Inc.
• Public title: A Multi-Centre, Open-Label, Single Arm Trial to Evaluate Efficacy, Pharmacokinetics, and Safety and Tolerability of IGSC 20% in Subjects with Primary Immunodeficiency
• Scientific title: A Multi-Centre, Open-Label, Single Arm Trial to Evaluate Efficacy, Pharmacokinetics, and Safety and Tolerability of IGSC 20% in Subjects with Primary Immunodeficiency - GTI1503
• Date of first enrolment: 12/05/2016
• Target sample size: 60
• Recruitment status: Not Recruiting
• URL: https://www.clinicaltrialsregister.eu/ctr-search/search?query=eudract_number:2015-003290-15
• Study type: Interventional clinical trial of medicinal product
• Study design: Controlled: no; Randomised: no; Open: yes; Single blind: no; Double blind: no; Parallel group: no; Cross over: no; Other: no; If controlled, specify comparator, Other Medicinial Product: no; Placebo: no; Other: Number of treatment arms in the trial: 1
• Phase: Human pharmacology (Phase I): no Therapeutic exploratory (Phase II): no Therapeutic confirmatory - (Phase III): yes Therapeutic use (Phase IV): no

Countries of recruitment

Australia, Czech Republic, France, Germany, Hungary, Poland, Spain, Sweden, United Kingdom

Contacts

• Name: Elsa Mondou
• Affiliation: Grifols Therapeutics Inc.

• Name: Elsa Mondou
• Affiliation: Grifols Therapeutics Inc.

Key inclusion & exclusion criteria

Inclusion criteria:
1. Adults and adolescents between the ages of 2 and 75 years (inclusive) at Screening.
2. Documented and confirmed pre-existing diagnosis of PI with features of hypogammaglobulinemia requiring IgG replacement therapy including
but not limited to the following: humoral-based immunodeficiency syndromes (e.g., X-linked agammaglobulinemia, common variable immunodeficiency), and combined immunodeficiency syndromes without lymphocytopenia (e.g., hyper immunoglobin [IgM] immunodeficiency syndrome). Please also refer to Exclusion Criteria.
3. The subject has not had an SBI within the last 3 months prior to Screening and has no SBI up to the time of the Baseline Visit.
Note: if an SBI occurs during the Screening/Previous Regimen Phase and prior to the first dose of Grifols IGSC 20%, the subject will be a
Screen Failure
4. Currently on IgG replacement therapy (stable regimen [dose and dosing interval] via IV or SC infusion) for = 3 consecutive months.
Subjects receiving IVIG prior to study must receive a dosage of at least 200 mg/kg per infusion.
5. Documentation (within previous 6 months) of an IgG trough level of = 500 mg/dL on current IgG replacement therapy regimen.
6. Screening/pre-Baseline trough IgG levels must be = 500 mg/dL. Note: If Screening and/or pre-Baseline trough levels (not including
pSC#2 trough) are not above this threshold the subject will be a Screen Failure, but may be re-screened following dose adjustment of their
original IgG replacement therapy regimen and maintaining stable dosing for a period of at least 3 consecutive months prior to Screening a second
time.
7. The medical records for all subjects should be available to document diagnosis, previous infections and treatment.
8. The subject has signed an informed consent. Note: The subject must sign the informed consent form (ICF) if at least 18 years old; for children of younger age the subject's parent or legal guardian must sign the ICF and if appropriate/applicable, the subject must sign a Child Assent form approved by the Institutional Review Board or Ethics Committee (IRB/EC) per their requirements

Are the trial subjects under 18? yes
Number of subjects for this age range: 20
F.1.2 Adults (18-64 years) yes
F.1.2.1 Number of subjects for this age range 20
F.1.3 Elderly (>=65 years) yes
F.1.3.1 Number of subjects for this age range 10

Exclusion criteria:
1. Clinical evidence of any significant acute or chronic disease that, in the opinion of the PI, may interfere with successful completion of the trial or place the subject at undue medical risk
2. The subject has had a known SAE to immunoglobulin or any severe anaphylactic reaction to blood or any blood-derived product
3. The subject has a history of blistering skin disease, clinically significant thrombocytopenia, bleeding disorder, diffuse rash, recurrent skin infections, or other disorders where SC therapy would be contraindicated during the study
4. The subject has isolated IgG subclass deficiency, isolated specific antibody deficiency disorder, or transient hypogammaglobulinemia of
infancy
5. The subject has known Selective Immunoglobulin A (IgA) Deficiency (with or without antibodies to IgA). (Note: exclusion is for the specific
diagnostic entity. It does not exclude other forms of humoral primary immunodeficiency which have decreased IgA in addition to decreased
IgG requiring immune globulin [IgG] replacement)
6. Females of childbearing potential who are pregnant, have a positive pregnancy test at Screening (serum) or Baseline (urine) (human
chorionic gonadotropin [HCG]-based assay), are breastfeeding, or unwilling to practice a highly effective method of contraception (oral,
injectable or implanted hormonal methods of contraception, placement of an intrauterine device [IUD] or intrauterine system [IUS], condom or occlusive cap with spermicidal foam/gel/film/cream/suppository, male sterilization, or true abstinence) throughout the study
7. The subject has significant proteinuria (dipstick proteinuria = 3+, known urinary protein loss > 1 g/24 hours, or nephrotic syndrome), has
a history of acute renal failure, has severe renal impairment (blood urea nitrogen [BUN] or creatinine more than 2.5 times the upper limit of
normal [ULN]), and/or is on dialysis
8. The subject has Screening Visit values of aspartate aminotransferase (AST) or alanine aminotransferase (ALT) levels exceeding 2.5 times the
ULN for the expected normal range for the testing laboratory
9. The subject has hemoglobin < 9 g/dL at Screening
10. The subject has a known previous infection with or clinical signs and symptoms consistent with current hepatitis B virus (HBV) or hepatitis C
virus (HCV) infection
11. 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
12. The subject is currently receiving anti-coagulation therapy which would make SC administration inadvisable (vitamin K antagonists,
nonvitamin K antagonist oral anticoagulants
13. The subject currently has a known hyperviscosity syndrome
14. The subject has an acquired medical condition that is known to cause secondary immune deficiency, such as chronic lymphocytic
leukemia, lymphoma, multiple myeloma, chronic or recurrent neutropenia (absolute neutrophil count less than 1000/µL [1.0 x
109/L]), or HIV infection/AIDS
15. The subject is HIV positive by NAT based on a Screening blood sample. The subject may enter the Previous Regimen Phase while the
Screening blood sample is being tested, but will be a Screen Failure and will not undergo Baseline assessments if the HIV result is positive
16. Subjects under 18 years of age have non-controlled arterial hypertension at a level of greater than or equ

Age minimum:
Age maximum:
Gender:
Female: yes
Male: yes

Health Condition(s) or Problem(s) studied

Primary Immunodeficiency (PI) diseases
MedDRA version: 20.0 Level: PT Classification code 10061598 Term: Immunodeficiency System Organ Class: 10021428 - Immune system disorders
MedDRA version: 20.0 Level: LLT Classification code 10045792 Term: Unspecified disorder of immune mechanism System Organ Class: 10021428 - Immune system disorders
MedDRA version: 20.0 Level: PT Classification code 10064859 Term: Primary immunodeficiency syndrome System Organ Class: 10010331 - Congenital, familial and genetic disorders

Therapeutic area: Body processes [G] - Immune system processes [G12]

Intervention(s)

Product Name: Immune Globulin Subcutaneous (Human), 20% Caprylate/Chromatography Purified (IGSC 20%)
Product Code: IGSC 20%
Pharmaceutical Form: Solution for infusion
INN or Proposed INN: Immune Globulin Subcutaneous (Human), 20%, Caprylate/Chromatography Purified
Current Sponsor code: GRF6017
Concentration unit: % percent
Concentration type: equal
Concentration number: 20-

Primary Outcome(s)

Main Objective: The primary objective of this Phase 3 study is to evaluate whether weekly administered IGSC 20% over a one year period will achieve less than 1 SBI per subject per year in PI subjects.

Secondary Objective: • To determine if IGSC 20% replacement therapy maintains mean trough IgG levels that are comparable to the mean trough blood levels with previous IgG replacement regimen
• To evaluate trough levels of IgG subclasses
• To evaluate antibody levels for Streptococcus pneumoniae, Hemophilus influenzae, and Clostridium tetani
• To evaluate the PK profile in adult PI subjects at steady state (after approximately 4 months [16 weeks]) of weekly administration of IGSC 20%
• Trough measles antibody titers (functional assay) are an exploratory variable for informational purposes
• To evaluate validated infections documented by positive radiograph, fever (> 38°C oral or > 39°C rectal), culture, or diagnostic testing for microorganisms e.g., bacterial, viral, fungal, or protozoal pathogens
• To evaluate no. of days on antibiotics, no. hospitalizations and no. days work/school/activities missed due to infections
• To assess the safety and tolerability of IGSC 20%

Primary end point(s): The primary efficacy variable is the number of SBIs. Also, the percentage of subjects with SBIs will be summarized.

Timepoint(s) of evaluation of this end point: Sampling will be taken throughout Previous Regimen Phase and Treatment Phases 1 and 2.

Secondary Outcome(s)

Timepoint(s) of evaluation of this end point: Sampling will be taken throughout Previous Regimen Phase and Treatment Phases 1 and 2.

Secondary end point(s): The secondary endpoint of this study is trough concentrations of total IgG of previous regimen during the Screening/Previous Regimen Phase and the IGSC 20% Treatment Stages. It is measured to determine if IGSC 20% replacement therapy maintains mean trough IgG levels that are comparable to the mean trough blood levels with the previous IgG replacement regimen.

Additional PK parameters include average trough concentration of IgG subclasses (IgG1, IgG2, IgG3, and IgG4), and concentration of antibody levels to S. pneumoniae, H. influenzae, and C. tetani (tetanus). Trough measles antibody titers (functional assay) are an exploratory variable for informational purposes.
For the adult (n~20) PK subset, serial samples will be collected immediately before and after SC#17 infusion at steady state. The PK profile will include total IgG concentrations at timepoints over a 7-day period. PK parameters including AUC0-7days, Cmax, and tmax will be determined by a noncompartmental model using WinNonlin.

Other efficacy variables include rate of infection of any kind (serious and non-serious) including acute sinusitis, exacerbation of chronic sinusitis, acute otitis media, pneumonia, acute bronchitis, infectious diarrhea, etc., which will be recorded as an AE with the Investigator answering the following question affirmatively in the eCRF: “Is this an infection? (verbatim term delineating nature of infection). Validated infections documented by positive radiograph, fever (> 38°C oral or > 39°C rectal), culture, or diagnostic testing for microorganisms e.g., bacterial, viral, fungal, or protozoal pathogens (for instance, rapid streptococcal antigen test) will be analyzed separately.
In addition, details regarding infections will include antibiotic treatment (oral, parenteral, oral plus parenteral, prophylactic, and therapeutic), and hospitalizations due to infection. Days lost from work/school/daily activities due to infections and related treatment comprise additional variables.

Secondary ID(s)

GTI1503

Source(s) of Monetary Support

Grifols Worldwide Operations Ltd

Ethics review

Status: Approved
Approval date: 12/05/2016
Contact:

Results

• Results available: Yes
• Date Posted: 13/03/2020
• Date Completed: 15/05/2019
• URL: https://www.clinicaltrialsregister.eu/ctr-search/trial/2015-003290-15/results