Clinical Trials Register

Summary
EudraCT Number:	2021-000580-78
Sponsor's Protocol Code Number:	EMPAtia
National Competent Authority:	Poland - Office for Medicinal Products
Clinical Trial Type:	EEA CTA
Trial Status:	Ongoing
Date on which this record was first entered in the EudraCT database:	2021-04-19
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

Poland - Office for Medicinal Products

A.2

EudraCT number

2021-000580-78

A.3

Full title of the trial

"The assessment of effectiveness and safeness of utilizing empagliflozin in the treatment of neutropenia of patients suffering from glycogenolysis type Ib"

„Ocena skuteczności i bezpieczeństwa empagliflozyny w leczeniu neutropenii u pacjentów z glikogenozą Ib”

A.3.1

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

"The assessment of effectiveness and safeness of utilizing empagliflozin in the treatment of neutropenia of patients suffering from glycogenolysis type Ib"

„Ocena skuteczności i bezpieczeństwa empagliflozyny w leczeniu neutropenii u pacjentów z glikogenozą Ib”

A.3.2

Name or abbreviated title of the trial where available

EMPAtia

A.4.1

Sponsor's protocol code number

EMPAtia

A.7

Trial is part of a Paediatric Investigation Plan

A.8

EMA Decision number of Paediatric Investigation Plan

B. Sponsor Information
B.Sponsor: 1
B.1.1	Name of Sponsor	The Children’s Memorial Health Institute
B.1.3.4	Country	Poland
B.3.1 and B.3.2	Status of the sponsor	Non-Commercial
B.4 Source(s) of Monetary or Material Support for the clinical trial:
B.4.1	Name of organisation providing support	Medical Research Agency
B.4.2	Country	Poland
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	The Children’s Memorial Health Institute
B.5.2	Functional name of contact point	Dariusz Rokicki
B.5.3	Address:
B.5.3.1	Street Address	Av. Dzieci Polskich 20
B.5.3.2	Town/ city	Warsaw
B.5.3.3	Post code	04-730
B.5.3.4	Country	Poland
B.5.4	Telephone number	48228157545
B.5.6	E-mail	d.rokicki@ipczd.pl

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	Yes
D.2.1.1.1	Trade name	Jardiance, empagliflozin, 10 mg film- coated tablets
D.2.1.1.2	Name of the Marketing Authorisation holder	Boehringer Ingelheim International GmbH
D.2.1.2	Country which granted the Marketing Authorisation	Poland
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	Jardiance
D.3.4	Pharmaceutical form	Film-coated tablet
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Oral use
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	Yes
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	No
	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

neutropenia and / or abnormal neutrophil function in glycogenosis I b

neutropenia i /lub nieprawidłowa funkcja neutrofilów w przebiegu glikogenozy I b

E.1.1.1

Medical condition in easily understood language

decreased concentration of neutrophils and / or their malfunction in the course of glycogenosis Ib

obniżone stężenie neutrofili i/lub ich nieprawidłowe działanie w przebiegu glikogenozy I b

E.1.1.2

Therapeutic area

Diseases [C] - Nutritional and Metabolic Diseases [C18]

MedDRA Classification

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 goal of the research is to assess safeness and tolerance of treating neutropenia with empagliflozin in the case of patients suffering from glycogen storage disease type Ib.

Celem pierwszorzędowym badania jest ocena bezpieczeństwa i tolerancji leczenia neutropenii empagliflozyną u pacjentów z GSD Ib.

E.2.2

Secondary objectives of the trial

The secondary goal is the assessment of the effectiveness expressed as restoring the count and functioning of neutrophils. The tertiary goal is reducing/stopping dosage of filgrastym and thus limiting the undesirable effects related to the treatment utilizing filgrastym. The quaternary goal will be the assessment of the metabolic control.

Celem drugorzędowym jest ocena skuteczności wyrażona jako przywrócenie liczby i funkcji neutrofili. Celem trzeciorzędowym jest zmniejszenie/zaprzestanie dawkowania filgrastimu, a przez to ograniczenie działań niepożądanych związanych z leczeniem filgrastimem. Celem czwartorzędowym będzie ocena wyrównania metabolicznego.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

The patients meeting all the criteria listed below will be included into the research:
- men and women
- older than 4 weeks
- biochemically and / or molecularly diagnosed glycogenosis Ib with neutropenia and / or abnormal NADPH oxidase activity in neutrophils
- expressing voluntary and informed consent by a statutory representative in the case of children below 13 years of age, a statutory representative and a patient in the case of children above 13 years of age and by a patient himself in the case of adult patients.

Do badania będą włączeni pacjenci spełniający wszystkie poniższe kryteria:
- mężczyźni i kobiety
- wiek powyżej 4 tygodni życia
- rozpoznana biochemicznie i/lub molekularnie glikogenoza Ib z neutropenią i/lub nieprawidłową aktywnością oksydazy NADPH w neutrofilach
- wyrażenie dobrowolnej, świadomej zgody przez przedstawiciela ustawowego w przypadku dzieci < 13 rż, przedstawiciela ustawowego i pacjenta w przypadku dzieci >=13 rż oraz samego pacjenta w przypadku dorosłych pacjentów.

E.4

Principal exclusion criteria

5. The following patients will not be included into the research:
- patients who are suspected of not cooperating, including the patients not arriving for follow-up examinations or not following dietary recommendations;
- suffering from chronic kidney disease with Estimated Glomerular Filtration Rate < 60 ml/min/1.73 m2
- suffering from urinary tract infection at the time of qualifying for the research (time criterion at the time of inclusion into the research, until the urinary tract infection treatment is concluded),
- participating in other clinical trials (grace period: 6 months counting from the conclusion of participation in other trials to the date of signing the Informed Consent Form),
- participating in other forms of medicinal experiments apart from the experimental
empagliflozin treatment (grace period: 24 months counting from the date of concluding participation in the experiment to the date of signing the Informed Consent Form).
- allergic to the administered drugs
- pregnant and breast-feeding women
- patients who did not give consent for participation in the research

Nie będą włączeni do badania pacjenci:
:- u których istnieje ryzyko braku współpracy, w tym ryzyko niezgłaszania się na badania kontrolne i nieprzestrzegania zaleceń dietetycznych;
- przewlekła choroba nerekz eGFR < 60 ml/min/1,73 m2
- zakażenie układu moczowego w chwili kwalifikacji (kryterium czasowe w czasie włączenia do badania, do czasu zakończenia leczenia ZUM),
- udział w innym badaniu klinicznym (okres karencji: 6 miesięcy od zakończenia uczestnictwa do dnia podpisania Formularza Świadomej Zgody),
- udział w eksperymencie leczniczym, poza eksperymentalnym leczeniem empagliflozyną (okres karencji: 24 miesiące od zakończenia uczestnictwa do dnia podpisania Formularza Świadomej Zgody).
- uczuleni na podawane leki
- kobiety ciężarne i karmiące piersią
- którzy nie wyrażą zgody na udział w badaniu

E.5 End points

E.5.1

Primary end point(s)

The primary End Point will be the assessment of safeness and tolerance of empagliflozin expressed as a type and a frequency of occurrence of undesirable reactions throughout the entire period of the research.

Pierwszorzędowym punktem końcowym będzie ocena bezpieczeństwa i tolerancji empagliflozyny wyrażona jako rodzaj i częstość występowania reakcji niepożądanych w całym okresie badania.

E.5.1.1

Timepoint(s) of evaluation of this end point

The data pertaining to safeness will be collected during all examination appointments and will be cross-referenced with the possible undesirable effects of empagliflozin described in the characteristics of the medicinal product.

Dane dotyczące bezpieczeństwa będą zbierane podczas wszystkich wizyt i będą odnoszone do możliwych działań niepożądanych empagliflozyny opisanych w charakterystyce produktu leczniczego.

E.5.2

Secondary end point(s)

The secondary End Point will be the assessment of effectiveness of treatment of the neutropenia of patients suffering from glycogen storage disease type 1b expressed as:
- the percentage of patients taking empagliflozin who achived the neutrophils count in bloodat the level of >= 500 cells/ul for the period of at least 6 months.
- the percentage of patients taking empagliflozin who were discovered to display the proper level of NADPH activity of the neutrophils isolated from the peripheral blood during the final examination,
- the percentage of patients taking empagliflozin who were discovered to display the decreased frequency of the bacterial and fungal infections requiring antibiotics treatments throughout the entire period of the empagliflozin treatment in comparison to the data from the period preceeding introduction of the treatment. This frequency shall be expressed as the number of antibiotic treatments/year,
- the percentage of patients taking empagliflozin who were discovered to display the decreased frequency of infection-related hospitalizations throughout the entire period of the empagliflozin treatment in comparison to the data from the period preceeding introduction of the treatment. This frequency shall be expressed as the number of infection-related hospitalizations/year.
- the percentage of patients taking empagliflozin who were discovered to display reduced average number of bowel discharge instances per day (calculated from the period of 7 days preceeding the most recent examination), the reduced frequency of helcosis/ulceration in the buccal cavity and the reduced concentration of the calprotectin median in feces (from the entire research period) in comparison to the data from the period preceding introduction of the treatment.
The tertiary End Point will be the assessment of the possibility for reducing the filgrastym dosage expressed as:
- the percentage of patients who after taking empagliflozin for a period of at least 6 months reduced the dose of filgrastym they were taking by at least 50% in comparison to the dose they were taking at the day of being included into the research.
The quaternary End Point will be the assessment of the metabolic control defined as lowering the median of the lactic acid and triglycerides from the entire period of the empagliflozin-based treatment in comparison to the median of the lactic acid and triglycerides concentration from the period of one year prior to introduction of the treatment as well as normalization of the uric acid concentration.

Drugorzędowym punktem końcowym będzie ocena skuteczności leczenia neutropenii w przebiegu GSD Ib wyrażona jako:
- odsetek pacjentów przyjmujących empagliflozynę, którzy osiągnęli liczby neutrofili we krwi >= 500 komórek/ul przez minimum 6 miesięcy.
- odsetek pacjentów przyjmujących empagliflozynę, u których stwierdzono prawidłowy poziom aktywności NADPH w neutrofilach izolowanych z krwi obwodowej podczas ostatniej wizyty,
- odsetek pacjentów przyjmujących empagliflozynę, u których stwierdzono zmniejszenie częstości infekcji bakteryjnych i grzybiczych wymagających antybiotykoterapii przez cały okres leczenia empagliflozyną, w stosunku do danych z okresu roku przed włączeniem leczenia. Częstość ta będzie wyrażona jako liczba kuracji antybiotykowych/rok,
- odsetek pacjentów przyjmujących empagliflozynę, u których stwierdzono zmniejszenie częstości hospitalizacji z powodu infekcji przez cały okres leczenia empagliflozyną, w stosunku do danych z okresu roku przed włączeniem leczenia. Częstość ta będzie wyrażona jako liczba hospitalizacji z powodu infekcji/rok,
- odsetek pacjentów przyjmujących empagliflozynę, u których stwierdzono zmniejszenie średniej ilości wypróżnień w ciągu doby (liczonej z 7 dni sprzed ostatniej wizyty), zmniejszenie częstości występowania owrzodzeń w jamie ustanej oraz obniżenie stężenia mediany kalprotektyny w kale (z okresu trwania badania) w stosunku do danych z okresu roku przed włączeniem leczenia.
Trzeciorzędowym punktem końcowym będzie ocena możliwości redukcji dawki filgrastimu wyrażona jako:
- odsetek pacjentów, u których przez co najmniej 6 miesięcy stosowania empagliflozyny nastąpiła redukcja dawki filgrastimu o co najmniej 50% dawki filgrastimu stosowanej w dniu włączenia do badania.
Czwartorzędowym punktem końcowym będzie ocena wyrównania metabolicznego definiowanego jako obniżenie mediany stężenia kwasu mlekowego i trójglicerydów z całego okresu leczenia empagliflozyną w stosunku do mediany ich stężeń z okresu roku przed włączeniem leczenia oraz normalizacja stężenia kwasu moczowego.

E.5.2.1

Timepoint(s) of evaluation of this end point

The assessment of the neutrophils level will be conducted during every follow-up examination appointment. The NADPH activity assessment will by conducted every 6 months. The Secondary End Point will be evaluated at the time of the final examination during the treatment.

Ocena poziomu neutrofili będzie wykonywana podczas każdej wizyty kontrolnej. Ocena aktywności NADPH będzie wykonywana co 6 miesięcy.
Momentem ewaluacji Drugorzędowego Punktu Końcowego będzie ostatnia wizyta w badaniu.

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

Yes

E.6.4

Safety

Yes

E.6.5

Efficacy

Yes

E.6.6

Pharmacokinetic

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

Yes

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)

Yes

E.7.3

Therapeutic confirmatory (Phase III)

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

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.8.3

The trial involves single site in the Member State concerned

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

E.8.6 Trial involving sites outside the EEA

E.8.6.1

Trial being conducted both within and outside the EEA

E.8.6.2

Trial being conducted completely outside of the EEA

E.8.7

Trial has a data monitoring committee

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

Ostatnia wizyta ostatniego pacjenta

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

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)

Yes

F.1.1.4.1

Number of subjects for this age range:

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)

Yes

F.1.2.1

Number of subjects for this age range:

F.1.3

Elderly (>=65 years)

Yes

F.1.3.1

Number of subjects for this age range:

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

Yes

F.3.3.1

Women of childbearing potential not using contraception

F.3.3.2

Women of child-bearing potential using contraception

Yes

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

Yes

F.3.3.6.1

Details of subjects incapable of giving consent

patients under 13 years of age

pacjenci poniżej 13 roku życia

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.4.2.2

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

Nie dotyczy

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

2022-02-02

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2021-03-31

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

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