Clinical Assessment of Pharmacokinetics, Efficacy, and Safety of 10% IVIg in Pediatric PID Patients (KIDCARES10)

A Phase III, Open-label, Prospective, Multicenter Study to Assess Efficacy, Safety, and Pharmacokinetics of Kedrion Intravenous Human Normal Immunoglobulin (IVIg) 10% in Pediatric Patients Affected by Primary Immunodeficiency Disease (PID)

The purpose of this study is to assess efficacy, safety and pharmacokinetics of Kedrion Immunoglobulin 10% (KIg10) in pediatric patients with Primary Immunodeficiency Disease (PID).

Inclusion Criteria:

1. Written informed consent/assent obtained from the patient and his/her parent(s) or legally acceptable representative indicating that they understand the purpose of and procedures required for the study and are willing to participate in it.

2. Confirmed clinical diagnosis of a PID as defined by 2017 International Union of Immunological Societies (IUIS) Phenotypic Classification for Primary Immunodeficiencies (Bousfiha A, 2018 - and subsequent revisions) and The European Society for Immunodeficiencies (ESID) Registry Working Definitions for the Clinical Diagnosis of Inborn Errors of Immunity (Seidel MG et al., 2019 - and subsequent revisions) and requiring treatment with IVIg. Documented agammaglobulinemia (defined as the total absence of one or more classes of antibodies) or hypogammaglobulinemia (defined as low levels of one or more classes [i.e., at least 2 standard deviations under the mean level per age]).

   (NOTE: IVIg treatment is generally requested in the absence of IgG independently from whether other antibodies are absent).

3. Male or female, age from 2 up to < 16 years, at the time of screening.

4. Received 200 to 800 mg/kg of a commercially available IVIg therapy in the range of 21- or 28-day intervals (±3 or ±4 days, respectively) for at least 3 infusions prior to screening.

   (NOTE: Other IVIgs will be prohibited after ICF signature and until study end, week 51/52).

5. At least 2 documented IgG trough levels while receiving an IVIg, of ≥ 6 g/L obtained at 2 infusions within 12 months (1 must be within 6 months) prior to ICF signature.

6. Patient and his/her parent(s)/legal guardian(s) are willing to comply with all requirements of the protocol.

7. Females of child-bearing potential with a negative pregnancy test (serum or urine) and who agree to employ adequate birth control measures during the study, such as:

   1. sexual abstinence, to be evaluated in relation to the preferred and usual lifestyle of the subject;
   2. male or female condom with or without spermicide;
   3. cap, diaphragm or sponge with spermicide;
   4. progestogen-only oral hormonal contraception, if already used in the past on medical prescription.

   Adequate birth control measures should be maintained throughout the study under parental control.

8. Authorization to access personal health information.

9. Patients previously participating in a clinical trial with another experimental IVIg may be enrolled if they have received stable commercially available IVIg therapy for at least 3 infusions (21 or 28 days) prior to screening.

10. Patients currently on treatment with any subcutaneous immunoglobulin (SCIG) can be enrolled if they are switched to stable commercially available IVIg therapy for at least 3 infusions (21 or 28 days) prior to screening.

11. Males or females with a body weight greater than or equal to 15 kg (≥ 15 kg).

Exclusion Criteria:

1. Newly diagnosed PID and naïve to IgG replacement therapy.

2. Dysgammaglobulinemia (defined as a deficiency in one or more classes of antibodies, but not severe enough to require substitutive therapy) or isolated IgG subclass deficiency, or profound primary T cell deficiency (defined as the absence or severe reduction of T lymphocytes [CD3+ < 300 cell/mm3] and an absent or particularly low proliferative response [10% of the lower normal range] to phytohaemagglutinin P [PHA]).

3. History of severe or serious reactions or hypersensitivity to IVIg or other injectable forms of IgG.

4. History of thrombotic events including deep vein thrombosis, cerebrovascular accident, pulmonary embolism, transient ischemic attacks, or myocardial infarction, as defined by at least 1 event in patient's lifetime.

5. IgA deficiency with documented antibodies to IgA.

6. Received blood products that have not undergone viral inactivation measures within 12 months prior to ICF signature.

7. Significant protein losing enteropathy, nephrotic syndrome, or lymphangiectasia.

8. An acute infection as documented by culture or diagnostic imaging and/or a body temperature ≥38.5 °C (≥101.3 °F) within 7 days prior to screening.

9. Acquired immunodeficiency syndrome (AIDS) and/or hepatitis B/C active disease at ICF signature.

10. Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) > 2.5 times of the upper limit of normal for the laboratory designated for the study.

11. Using an implanted venous access device.

12. Moderate or severe anemia, defined according to patient's age as shown in the following table (World Health Organization, 2011) or persistent severe neutropenia (≤ 500 neutrophils per mm3) or persistent lymphopenia of less than 500 cells per microliter.

13. A severe chronic condition such as renal failure [defined as abnormalities in kidney structure or function that are present for more than 3 months and have health implications. The disease is classified on the basis of cause and category of glomerular filtration rate (GFR) (G1 to G5) and albuminuria (A1 to A3) (KIDIGO, 2017). See the following table], congestive heart failure (New York Heart Association III/IV), cardiomyopathy, cardiac arrhythmia associated with thromboembolic events (e.g., atrial fibrillation), unstable or advanced ischemic heart disease, hyperviscosity, or any other condition that the Investigator believes is likely to interfere with evaluation of the study drug or with satisfactory conduct of the trial.

14. History of a malignant disease other than properly treated carcinoma in situ of the cervix or basal cell or squamous cell carcinoma of the skin within 24 months prior to ICF signature.

15. History of pharmacoresistant epilepsy or multiple episodes of migraine (defined as at least 1 episode within 6 months of ICF signature) not controlled by medication.

16. Patient must not be receiving the following medication from at least 30 days prior to ICF signature:

    1. Steroids, inhaled, oral or parenteral, at a daily dosage of ≥ 0.15 mg/kg/day of prednisone or equivalent).
    2. Other immunosuppressive drugs (including monoclonal antibodies) or chemotherapy.

17. Females who are pregnant, breast feeding or planning a pregnancy during the course of the study. Women who become pregnant during the study will be withdrawn from the study.

18. Participated in another clinical study within 30 days prior to ICF signature.

19. Active drug or alcohol abuse or history of drug or alcohol abuse within the 6 months before screening.

20. Direct relative of an employee of the CRO, the study site, or Kedrion.

21. Previously treated under this protocol.

22. Unable to provide informed consent.

23. Patients with any condition which, in the opinion of the Investigator, might interfere with the evaluation of the study objectives or the patient's participation in this trial.

24. Patients with Hypersensitivity to the active substance or to any of the excipients.