Clinical Trials Register

Summary
EudraCT Number:	2020-001496-32
Sponsor's Protocol Code Number:	KB070
National Competent Authority:	Hungary - National Institute of Pharmacy
Clinical Trial Type:	EEA CTA
Trial Status:	Ongoing
Date on which this record was first entered in the EudraCT database:	2020-07-02
Trial results

Index
A. PROTOCOL INFORMATION
B. SPONSOR INFORMATION
C. APPLICANT IDENTIFICATION
D. IMP IDENTIFICATION
D.8 INFORMATION ON PLACEBO
E. GENERAL INFORMATION ON THE TRIAL
F. POPULATION OF TRIAL SUBJECTS
G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
P. END OF TRIAL

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A. Protocol Information

A.1

Member State Concerned

Hungary - National Institute of Pharmacy

A.2

EudraCT number

2020-001496-32

A.3

Full title of the trial

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)

III. fázisú, nyílt elrendezésű, prospektív, multicentrikus vizsgálat a Kedrion 10% os intravénás humán normál immunglobulin (IVIg) hatásosságának, biztonságosságának és farmakokinetikájának értékelésére primer immunhiányos betegségben szenvedő gyermekgyógyászati betegeknél (PID)

A.3.1

Title of the trial for lay people, in easily understood, i.e. non-technical, language

Study, in which all know the treatment assigned to the patient, conducted in more sites, to evaluate the efficaty, safety, and metabolism of Kedrion in venous Human Normal Immunoglobulin (IVIg) 10% in child with Primary Immunodeficiency Disease (PID)

A.3.2

Name or abbreviated title of the trial where available

PID-PED study

A.4.1

Sponsor's protocol code number

KB070

A.7

Trial is part of a Paediatric Investigation Plan

Yes

A.8

EMA Decision number of Paediatric Investigation Plan

P/246/2017

B. Sponsor Information
B.Sponsor: 1
B.1.1	Name of Sponsor	KEDRION S.P.A
B.1.3.4	Country	Italy
B.3.1 and B.3.2	Status of the sponsor	Commercial
B.4 Source(s) of Monetary or Material Support for the clinical trial:
B.4.1	Name of organisation providing support	Pharmaceutical company, KEDRION S.p.A
B.4.2	Country	Italy
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Cromsource S.r.l
B.5.2	Functional name of contact point	Clinical Research Department
B.5.3	Address:
B.5.3.1	Street Address	Via Giorgio De Sandre 3
B.5.3.2	Town/ city	Verona
B.5.3.3	Post code	37135
B.5.3.4	Country	Italy
B.5.4	Telephone number	39 0458222811
B.5.5	Fax number	390458222812
B.5.6	E-mail	oriana.zerbini@cromsource.com

D. IMP Identification
D.IMP: 1
D.1.2 and D.1.3	IMP Role	Test
D.2	Status of the IMP to be used in the clinical trial
D.2.1	IMP to be used in the trial has a marketing authorisation	No
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.1	Product name	KIg10
D.3.2	Product code	KIg10
D.3.4	Pharmaceutical form	Concentrate and solvent for solution for infusion
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Intravenous use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	Human Immunoglobulin
D.3.9.2	Current sponsor code	KIg10
D.3.9.4	EV Substance Code	SUB127300
D.3.10	Strength
D.3.10.1	Concentration unit	mg/kg milligram(s)/kilogram
D.3.10.2	Concentration type	range
D.3.10.3	Concentration number	200 to 800
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	No
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	Yes
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	No
D.3.11.3.1	Somatic cell therapy medicinal product	No
D.3.11.3.2	Gene therapy medical product	No
D.3.11.3.3	Tissue Engineered Product	No
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	No
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	No
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	No
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	No
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	No
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	No

D.8 Information on Placebo

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

Pediatric Patients Affected by Primary Immunodeficiency Disease.

E.1.1.1

Medical condition in easily understood language

Child with Immunodeficiency Disease.

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	20.0
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

E.2 Objective of the trial

E.2.1

Main objective of the trial

Primary Efficacy Objective
To assess the efficacy of KIg10 administered to patients with PID to demonstrate that the rate of acute serious bacterial infections (i.e., the mean number of acute serious bacterial infections per patient-year) is less than 1.0 to provide substantial evidence of efficacy from day 1 to week 51/52.
Safety Objective
To assess the safety of KIg10 in the overall study population from day 1 to week 51/52.
Pharmacokinetic Objectives
To assess the distribution, metabolism, and elimination of KIg10, total IgG, IgG subclasses, and antigen-specific IgGs at steady state in PID patients treated at different dosing schedules.
To evaluate trough concentrations of total IgG and compare to trough concentrations prior to the study entry.

E.2.2

Secondary objectives of the trial

Levels:
• Of IgG trough before each infusion and at the study termination visit.
• Of IgG subclasses before infusions 1, 5, 9, and 13 for the 28-day infusion schedule
and at infusions 1, 7, 11, and 17 for the 21-day infusion schedule.
• Of Anti-tetanus toxoid, anti-pneumococcal capsular polysaccharide, anti Haemophilus influenza, and anti-measles antibodies 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.
Occurrence and duration of any infection other than acute serious bacterial infections, of fever episodes, of overall hospitalization, of hospitalization due to infection,
of patients on antibiotics for the treatment of any kind of infections from day 1 to week 51/52.
The missed days of work/school/other major activities due to infections, from day 1 to week 51/52.
QoL using the PedsQL™ questionnaires collected at baseline, at 24 weeks, and at the study termination visit.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1. Written informed consent/assent obtained from the patient and his/her parent(s) or egally 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 The European Society for Immunodeficiencies (ESID) Registry
Working Definitions for the Clinical Diagnosis of Inborn Errors of Immunity (Seidel MG at al., 2019) 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 [ie, 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 and 11 months, at the time of screening, as the patient must be under 18 years (< 18) at the time of study termination visit.
4. Received 200 to 800 mg/kg of a commercially available IVIg therapy in the range of 1- or 28-day intervals (±3 or ±4 days, respectively) for at least 3 infusion cycles 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 infusion cycles within 12 months (1 must be within 6 months) prior to ICF ignature.
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.
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 infusion cycles (21 or 28 days) prior to screening.
10. Patients currently on treatment with any subcutaneous immunoglobulin (SCIG) can be nrolled if they are switched to stable commercially available IVIg therapy for at least 3 infusion cycles (21 or 28 days) prior to screening.

E.4

Principal exclusion criteria

Newly diagnosed PID and naïve to IgG replacement therapy.
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]).
History of severe or serious reactions or hypersensitivity to IVIg or other injectable forms of IgG.
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.
IgA deficiency with documented antibodies to IgA.
Received blood products that have not undergone viral inactivation measures within 12 months prior to ICF signature.
Significant protein losing enteropathy, nephrotic syndrome, or lymphangiectasia.
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.
Acquired immunodeficiency syndrome (AIDS) and/or hepatitis B/C active disease at ICF signature.
Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) > 2.5 times of the upper limit of normal for the laboratory designated for the study.
Using an implanted venous access device.
Profound anemia, defined according to the patient's age as shown in table Dallman PR, 1979 or persistent severe neutropenia (= 500 neutrophils per mm3) or persistent lymphopenia of less than 500 cells per microliter.
A severe chronic condition such as renal failure, 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.
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.
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.
Patient must not be receiving the following medication from at least 30 days prior to ICF signature:
Steroids, oral or parenteral, at a daily dose of = 0.15 mg/kg/day of prednisone or equivalent).
Other immunosuppressive drugs (including monoclonal antibodies) or chemotherapy.
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.
Participated in another clinical study within 30 days prior to ICF signature.
Active drug or alcohol abuse or history of drug or alcohol abuse within the 6 months before screening.
Direct relative of an employee of the CRO, the study site, or Kedrion.
Previously treated under this protocol.
Unable to provide informed consent.
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.

E.5 End points

E.5.1

Primary end point(s)

Incidence rate (i.e., the mean number of acute serious bacterial infections per patientyear) of acute serious bacterial infections (bacterial pneumonia, bacteremia/sepsis, bacterial meningitis, visceral abscess, osteomyelitis/septic arthritis) according to
pre-specified criteria). Primary analysis of the primary endpoint will be performed on the FAS. Primary efficacy will be analyzed using a Poisson model using as offset the length of the observation period per patient. The estimate and 1-sided 99% upper confidence limit
will be reported. Efficacy will be claimed if this limit is less than 1.0.

E.5.1.1

Timepoint(s) of evaluation of this end point

All visits

E.5.2

Secondary end point(s)

1. Serum IgG trough levels before each infusion of KIg10 and at the study termination visit (week 51/52).
2. IgG subclasses levels (IgG1, IgG2, IgG3, IgG4) 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.
3. Frequency of patients with total IgG below 6 g/L criteria.
4. Anti-tetanus toxoid antibody level (quantitative assay) 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.
5. Anti-pneumococcal capsular polysaccharide antibody level (quantitative assay) 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.
6. Anti-measles antibody level (quantitative assay) 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.
7. Anti-Haemophilus influenza type b antibody level (quantitative assay) 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.
8. Incidence rate (i.e., the mean number per patient-year) of any infection other than acute serious bacterial infections from day 1 to week 51/52.
9. Duration of any infection other than acute serious bacterial infections from day 1 to week 51/52.
10.Incidence rate (i.e. the mean number per patient-year) of fever episodes, from day 1 to week 51/52.
11.Duration of fever episodes, from day 1 to week 51/52.
12.Overall hospitalization days from day 1 to week 51/52.
13.Days of hospitalizations due to infection from day 1 to week 51/52.
14.Incidence rate (i.e. the mean number per patient-year) of patient on antibiotics
for the treatment of any kind of infection from day 1 to week 51/52.
15.Duration of patients on antibiotics for the treatment of any kind of infection from day 1 to week 51/52.
16.Days of missed work/school/other major activities due to infections from day 1 to week 51/52.
17.PedsQL™ score at baseline, week 24, and study termination visit.

E.5.2.1

Timepoint(s) of evaluation of this end point

All visits

E.6 and E.7 Scope of the trial

E.6

Scope of the trial

E.6.1

Diagnosis

E.6.2

Prophylaxis

E.6.3

Therapy

E.6.4

Safety

Yes

E.6.5

Efficacy

Yes

E.6.6

Pharmacokinetic

Yes

E.6.7

Pharmacodynamic

E.6.8

Bioequivalence

E.6.9

Dose response

E.6.10

Pharmacogenetic

E.6.11

Pharmacogenomic

E.6.12

Pharmacoeconomic

E.6.13

Others

E.7

Trial type and phase

E.7.1

Human pharmacology (Phase I)

E.7.1.1

First administration to humans

E.7.1.2

Bioequivalence study

E.7.1.3

Other

E.7.1.3.1

Other trial type description

E.7.2

Therapeutic exploratory (Phase II)

E.7.3

Therapeutic confirmatory (Phase III)

Yes

E.7.4

Therapeutic use (Phase IV)

E.8 Design of the trial

E.8.1

Controlled

E.8.1.1

Randomised

E.8.1.2

Open

Yes

E.8.1.3

Single blind

E.8.1.4

Double blind

E.8.1.5

Parallel group

E.8.1.6

Cross over

E.8.1.7

Other

E.8.2

Comparator of controlled trial

E.8.2.1

Other medicinal product(s)

E.8.2.2

Placebo

E.8.2.3

Other

E.8.2.4

Number of treatment arms in the trial

E.8.3

The trial involves single site in the Member State concerned

Yes

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

E.8.5

The trial involves multiple Member States

Yes

E.8.5.1

Number of sites anticipated in the EEA

E.8.6 Trial involving sites outside the EEA

E.8.6.1

Trial being conducted both within and outside the EEA

Yes

E.8.6.2

Trial being conducted completely outside of the EEA

E.8.6.3

If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned

Hungary

Italy

Portugal

Russian Federation

Slovakia

E.8.7

Trial has a data monitoring committee

Yes

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

LVLS

E.8.9 Initial estimate of the duration of the trial

E.8.9.1

In the Member State concerned years

E.8.9.1

In the Member State concerned months

E.8.9.1

In the Member State concerned days

E.8.9.2

In all countries concerned by the trial years

E.8.9.2

In all countries concerned by the trial months

E.8.9.2

In all countries concerned by the trial days

F. Population of Trial Subjects

F.1 Age Range

F.1.1

Trial has subjects under 18

Yes

F.1.1

Number of subjects for this age range:

F.1.1.1

In Utero

F.1.1.2

Preterm newborn infants (up to gestational age < 37 weeks)

F.1.1.3

Newborns (0-27 days)

F.1.1.4

Infants and toddlers (28 days-23 months)

F.1.1.5

Children (2-11years)

Yes

F.1.1.5.1

Number of subjects for this age range:

F.1.1.6

Adolescents (12-17 years)

Yes

F.1.1.6.1

Number of subjects for this age range:

F.1.2

Adults (18-64 years)

F.1.3

Elderly (>=65 years)

F.2 Gender

F.2.1

Female

Yes

F.2.2

Male

Yes

F.3 Group of trial subjects

F.3.1

Healthy volunteers

F.3.2

Patients

Yes

F.3.3

Specific vulnerable populations

F.3.3.1

Women of childbearing potential not using contraception

F.3.3.2

Women of child-bearing potential using contraception

F.3.3.3

Pregnant women

F.3.3.4

Nursing women

F.3.3.5

Emergency situation

F.3.3.6

Subjects incapable of giving consent personally

F.3.3.7

Others

F.4 Planned number of subjects to be included

F.4.1

In the member state

F.4.2

For a multinational trial

F.4.2.1

In the EEA

F.4.2.2

In the whole clinical trial

F.5

Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)

None

G. Investigator Networks to be involved in the Trial

N. Review by the Competent Authority or Ethics Committee in the country concerned

Competent Authority Decision

Authorised

Date of Competent Authority Decision

2020-09-09

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2020-08-29

P. End of Trial
P.	End of Trial Status	Ongoing

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