Clinical trial NCT04944979: Clinical Assessment of Pharmacokinetics, Efficacy, and Safety of 10% IVIg in Pediatric PID Patients (KIDCARES10)
Official title: 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)
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE3
Conditions: Primary Immunodeficiency Disease
Keywords: Immunoglobulin
Kedrion IVIG 10%
IgG Antibodies
Agammaglobulinemia
Hypogammaglobulinemia
Pediatric
Lead sponsor: Kedrion S.p.A.
Sponsor class: INDUSTRY
First posted: 2021-06-30
Enrollment: 30
Sex: ALL
Minimum age (years): 2
Maximum age (years): 16
Standard ages: CHILD
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: 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).


Eligibility criteria: 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.

Primary outcomes:
measure: Incidence Rate of Acute Serious Bacterial Infections
timeFrame: From Baseline (Day 1) up to week 51/52
Secondary outcomes:
measure: Serum Immunoglobulin G (IgG) trough levels
timeFrame: Before each infusion of KIg10 and at the study termination visit (Week 51/52)
measure: Immunoglobulin G (IgG) subclasses levels (IgG1, IgG2, IgG3, IgG4)
timeFrame: Before infusions 1, 5, 9 and 13 for the 28-day infusion schedule, and before infusions 1, 7, 11 and 17 for the 21-day infusion schedule
measure: Frequency of patients with total Immunoglobulin G (IgG) below 6 g/L
timeFrame: Day 1 up to week 51/52
measure: Anti-tetanus toxoid antibody level
timeFrame: Before infusions 1, 5, 9 and 13 for the 28-day infusion schedule and before infusions 1, 7, 11 and 17 for the 21-day infusion schedule
measure: Anti-pneumococcal capsular polysaccharide antibody level
timeFrame: Before infusions 1, 5, 9 and 13 for the 28-day infusion schedule and before infusions 1, 7, 11 and 17 for the 21-day infusion schedule
measure: Anti-measles antibody level
timeFrame: Before infusions 1, 5, 9 and 13 for the 28-day infusion schedule and before infusions 1, 7, 11 and 17 for the 21-day infusion schedule
measure: Anti-Haemophilus influenza type b antibody level
timeFrame: Before infusions 1, 5, 9 and 13 for the 28-day infusion schedule and before infusions 1, 7, 11 and 17 for the 21-day infusion schedule
measure: Incidence rate (i.e., the mean number per patient-year) of any infection other than acute serious bacterial infections
timeFrame: From day 1 to week 51/52
measure: Duration of any infection other than acute serious bacterial infections
timeFrame: From day 1 to week 51/52
measure: Incidence rate (i.e. the mean number per patient-year) of fever episodes
timeFrame: From day 1 to week 51/52
measure: Duration of fever episodes
timeFrame: From day 1 to week 51/52
measure: Overall hospitalization days
timeFrame: From day 1 to week 51/52
measure: Days of hospitalizations due to infection
timeFrame: From day 1 to week 51/52
measure: Incidence rate (i.e. the mean number per patient-year) of patient on antibiotics for the treatment of any kind of infection
timeFrame: From day 1 to week 51/52
measure: Duration of patients on antibiotics for the treatment of any kind of infection
timeFrame: From day 1 to week 51/52
measure: Days of missed work/school/other major activities due to infections
timeFrame: From day 1 to week 51/52
measure: Pediatric Quality of Life Inventory (Pedsql) Score
timeFrame: At baseline, week 24, and study termination visit
measure: Number of Adverse Events (%) and proportion of patients experiencing at least one Adverse Event (AE)
timeFrame: From Baseline (Day 1) up to Week 51/52
measure: Number of Serisous AEs (%) and proportion of patients experiencing at least one Serious Adverse Event (SAE)
timeFrame: From Baseline (Day 1) up to Week 51/52
measure: Number of related infusion AEs (%) occurring during infusion or within 1, 24, and 72 hours after the end of infusion, and proportion of patients experiencing at least one related infusion AE. at least 1 of such related infusion AE.
timeFrame: From Baseline (Day 1) up to Week 51/52
measure: The proportion and number of KIg10 infusions for which the infusion rate is decreased due to Adverse Events.
timeFrame: From Baseline (Day 1) up to Week 51/52
measure: Number and proportion of infusions with one or more infusion (temporally-associated) Adverse Event.
timeFrame: From Baseline (Day 1) up to Week 51/52
measure: Number of Participants with Changes from Baseline Values in Vital Signs, Physical Examinations, Safety Laboratory Tests (hematology, serum chemistry and urinalysis).
timeFrame: Up to Week 51/52
measure: The proportion and number of patients with a positive Coomb's test
timeFrame: Following infusion 7 for the 28-day infusion schedule and infusion 9 for the 21-day infusion schedule
measure: The proportion and number of patients with a positive urine hemosiderin test
timeFrame: Following infusion 7 for the 28-day infusion schedule and infusion 9 for the 21- day infusion schedule
measure: Serum haptoglobin level
timeFrame: Following infusion 7 for the 28-day infusion schedule and infusion 9 for the 21-day infusion schedule.
measure: Serum Total Immunoglobulin G (IgG) levels, IgG Subclasses Levels, and Selected Specific Antibody Levels
timeFrame: Before and after infusion 5 (28-day infusion schedule) or infusion 7 (21-day infusion schedule)
measure: Plasma Concentration - Time Curve Of Total Immunoglobulin G (IgG)
timeFrame: Before and after infusion 5 (28-day infusion schedule) or infusion 7 (21-day infusion schedule)
measure: Elimination Half-Life (t1/2) of Total Immunoglobulin G (IgG)
timeFrame: Before and after infusion 5 (28-day infusion schedule) or infusion 7 (21-day infusion schedule)
measure: Area Under the Plasma Concentration-time Curve From Time Zero to Time of the Last Quantifiable Concentration (AUC(0-T)) of Total Immunoglobulin G (IgG)
timeFrame: Before and after infusion 5 (28-day infusion schedule) or infusion 7 (21-day infusion schedule)
measure: Area Under the Plasma Concentration-time Curve (AUC) From Time Zero to Infinity (AUC[0-inf]) of Total Immunoglobulin G (IgG)
timeFrame: Before and after infusion 5 (28-day infusion schedule) or infusion 7 (21-day infusion schedule)
measure: Volume of Distribution of Total Immunoglobulin G (IgG)
timeFrame: Before and after infusion 5 (28-day infusion schedule) or infusion 7 (21-day infusion schedule)
measure: Maximum Observed Plasma Concentration (Cmax) Of Total IgG
timeFrame: Before and after infusion 5 (28-day infusion schedule) or infusion 7 (21-day infusion schedule)
measure: Time to Reach the Maximum Plasma Concentration (Tmax) of Total Immunoglobulin G (IgG)
timeFrame: Before and after infusion 5 (28-day infusion schedule) or infusion 7 (21-day infusion schedule)
measure: Elimination Rate Constant of Total Immunoglobulin G (IgG)
timeFrame: Before and after infusion 5 (28-day infusion schedule) or infusion 7 (21-day infusion schedule)
measure: Area Under the Concentration-Time Curve From Time Zero up to Time Tau (AUC0-Tau) of Total Immunoglobulin G (IgG)
timeFrame: Before and after infusion 5 (28-day infusion schedule) or infusion 7 (21-day infusion schedule)
measure: Plasma Concentration-Time Curve Of Specific Immunoglobulin G (IgG) Antibodies
timeFrame: Before and after infusion 5 (28-day infusion schedule) or infusion 7 (21-day infusion schedule)
measure: Elimination Half-Life (t1/2) of Specific IgG Antibodies
timeFrame: Before and after infusion 5 (28-day infusion schedule) or infusion 7 (21-day infusion schedule)
measure: Area Under the Plasma Concentration-time Curve From Time Zero to Time of the Last Quantifiable Concentration (AUC(0-T)) of Specific Immunoglobulin G (IgG) Antibodies
timeFrame: Before and after infusion 5 (28-day infusion schedule) or infusion 7 (21-day infusion schedule)
measure: Volume Of Distribution of Specific Immunoglobulin G (IgG) Antibodies
timeFrame: Before and after infusion 5 (28-day infusion schedule) or infusion 7 (21-day infusion schedule)
measure: Maximum Observed Plasma Concentration (Cmax) of Specific Immunoglobulin G (IgG) Antibodies
timeFrame: Before and after infusion 5 (28-day infusion schedule) or infusion 7 (21-day infusion schedule)
measure: Time to Reach the Maximum Plasma Concentration (Tmax) of Specific Immunoglobulin G (IgG) Antibodies
timeFrame: Before and after infusion 5 (28-day infusion schedule) or infusion 7 (21-day infusion schedule)
measure: Elimination Rate Constant of Specific Immunoglobulin G (IgG) Antibodies
timeFrame: Before and after infusion 5 (28-day infusion schedule) or infusion 7 (21-day infusion schedule)
measure: Area Under the Plasma Concentration-time Curve From Time Zero to Infinity (AUC[0-inf]) of Specific Immunoglobulin G (IgG) Antibodies
timeFrame: Before and after infusion 5 (28-day infusion schedule) or infusion 7 (21-day infusion schedule)
measure: Area Under the Concentration-Time Curve From Time Zero up to Time Tau (AUC0-Tau) of Specific Immunoglobulin G (IgG) Antibodies
timeFrame: Before and after infusion 5 (28-day infusion schedule) or infusion 7 (21-day infusion schedule)
Other outcomes:
Locations:
city: Chula Vista
country: United States
facility: Velocity Clinical Research - MedPharmics - Lafayette
state: California
city: San Francisco
country: United States
facility: Benioff Children&#39;s Hospital - Mission Bay
state: California
city: Centennial
country: United States
facility: IMMUNOe Health and Research Centers
state: Colorado
city: Shreveport
country: United States
facility: Louisiana State University Shreveport
state: Louisiana
city: Toledo
country: United States
facility: Asthma and Allergy Center - Toledo
state: Ohio
city: Tulsa
country: United States
facility: Vital Prospects Clinical Research Institute PC
state: Oklahoma
city: Budapest
country: Hungary
facility: Dél-Pesti Centrumkórház - Országos Hematológiai És Infektológiai Intézet
city: Brescia
country: Italy
facility: SST Spedali Civili di Brescia
city: Firenze
country: Italy
facility: Azienda Ospedaliero-Universitaria - Ospedale Pediatrico Meyer
city: Genova
country: Italy
facility: I.R.C.C.S. Istituto Giannina Gaslini
city: Milano
country: Italy
facility: Fondazione IRCCS Ca&#39; Granda Ospedale Maggiore Policlinic
city: Napoli
country: Italy
facility: Azienda Ospedaliera Universitaria &#34;Federico II&#34;
city: Roma
country: Italy
facility: Fondazione Policlinico Tor Vergata
city: Roma
country: Italy
facility: IRCCS Ospedale Pediatrico Bambino Gesù
city: Lisbon
country: Portugal
facility: Centro Hospitalar Lisboa Central - Hospital Dona Estefânia
city: Porto
country: Portugal
facility: Centro Hospitalar Universitário do Porto - Hospital Santo António
city: Moscow
country: Russian Federation
facility: Children&#39;s City Clinical Hospital No. 9 named after G.N. Speransky, Moscow City Health Department
city: Moscow
country: Russian Federation
facility: Dmitry Rogachev National Medical Research Center for Pediatric Hematology, Oncology and Immunology
city: Bratislava
country: Slovakia
facility: Národný ústav detských chorôb (National Institute of Pediatric Diseases)
Study officials:
affiliation: Azienda Ospedaliero-Universitaria Ospedale Pediatrico Meyer - Italy
name: Chiara Azzari
role: PRINCIPAL_INVESTIGATOR
References: