Clinical Trials Register

Summary
EudraCT Number:	2016-005210-22
Sponsor's Protocol Code Number:	BOOG-2017-02
National Competent Authority:	Netherlands - Competent Authority
Clinical Trial Type:	EEA CTA
Trial Status:	Prematurely Ended
Date on which this record was first entered in the EudraCT database:	2017-12-21
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

Netherlands - Competent Authority

A.2

EudraCT number

2016-005210-22

A.3

Full title of the trial

Explorative trial to identify the impact of denosumab on the systemic immunity and local immunologic microenvironment in postmenopausal patients with HER2 negative breast cancer.

Exploratieve studie om de impact van denosumab op de systemische immuniteit en het lokale immunologische micromilieu in postmenopauzale patiënten met HER2 negatieve borstkanker te bepalen.

A.3.1

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

The influence of denosumab on the immune system in women after the menopause with HER2 negative breastcancer.

De invloed van denosumab op het immuunsysteem bij vrouwen na de overgang met HER2 negatieve borstkanker.

A.3.2

Name or abbreviated title of the trial where available

PERIDENO study

PERIDENO studie

A.4.1

Sponsor's protocol code number

BOOG-2017-02

A.5.2

US NCT (ClinicalTrials.gov registry) number

NCT03532087

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	BOOG Study Center
B.1.3.4	Country	Netherlands
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	Amgen
B.4.2	Country	Netherlands
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Leiden University Medical Center
B.5.2	Functional name of contact point	Dr. J.R. Kroep
B.5.3	Address:
B.5.3.1	Street Address	P.O. Box 9600
B.5.3.2	Town/ city	Leiden
B.5.3.3	Post code	2300 RC
B.5.3.4	Country	Netherlands
B.5.4	Telephone number	00310715263464
B.5.6	E-mail	J.R.Kroep@lumc.nl

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	Prolia
D.2.1.1.2	Name of the Marketing Authorisation holder	Amgen Europe B.V.
D.2.1.2	Country which granted the Marketing Authorisation	Netherlands
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.3.4	Pharmaceutical form	Injection
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Subcutaneous use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	Denosumab
D.3.9.1	CAS number	615258-40-7
D.3.9.3	Other descriptive name	DENOSUMAB
D.3.9.4	EV Substance Code	SUB29173
D.3.10	Strength
D.3.10.1	Concentration unit	mg/ml milligram(s)/millilitre
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	60
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.IMP: 2
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	Xgeva
D.2.1.1.2	Name of the Marketing Authorisation holder	Amgen Europe B.V.
D.2.1.2	Country which granted the Marketing Authorisation	Netherlands
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.3.4	Pharmaceutical form	Injection
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Subcutaneous use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	Denosumab
D.3.9.1	CAS number	615258-40-7
D.3.9.3	Other descriptive name	DENOSUMAB
D.3.9.4	EV Substance Code	SUB29173
D.3.10	Strength
D.3.10.1	Concentration unit	mg/ml milligram(s)/millilitre
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	70
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

Mamma carcinoma

Mammacarcinoom

E.1.1.1

Medical condition in easily understood language

Breast cancer

Borstkanker

E.1.1.2

Therapeutic area

Diseases [C] - Cancer [C04]

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	10057654
E.1.2	Term	Breast cancer female
E.1.2	System Organ Class	10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)

E.1.3

Condition being studied is a rare disease

E.2 Objective of the trial

E.2.1

Main objective of the trial

Determine the change in intratumoral T-cell (CD4, CD8 and Treg) and Myeloid cell (M1/M2 Macrophage, MDSC, DC) numbers and function between the baseline biopsy and the surgical specimen.

Bepalen van de verandering in intratumorale T-cel (CD4, CD8 en Treg) en Myeloide cel (M1/M2 Macrofaag, MDSC, DC) aantallen en functie tussen het baseline biopt en chirurgisch specimen.

E.2.2

Secondary objectives of the trial

• PBMC before start treatment, at day of surgery and 7 days after last denosumab administration:
o Determine the shift in T-cell (activated T effector cells and regulatory T cells) levels and function in PBMC samples.
o Determine the change in mature and immature myeloid cells (M1, M2, MDSC, DC).
o Determine the shift in myeloid cell function (IL-10 and IL-12 production after LPS or anti-CD40 triggering).
o Determine the change in stimulation capacity APCs (MLR + cytokine production after restimulation).
• Serum before start treatment, at day of surgery and 7 days after last denosumab administration:
o Determine the change in RANKL, OPG by ELISA; TNF-alpha, IL-1-beta, IL-6, IL-7, IL-10, IL-15, IL-12, IFN gamma by luminex.
• Tumor
o Correlate tumor (biopsy and resection material), serum and PBMC immunologic parameters.
• Toxicity according to NCI CTCAE v4.03.
• Determine the descriptive difference in event-free survival (EFS) at 3 year based on immune response.

• PBMC voor start behandeling, dag van operatie en 7 dagen na laatste denosumab toediening:
o Bepalen van de shift in T-cell (geactiveerde T effector en regulatoire T cellen) levels en functie in PBMC samples.
o Bepalen van de verandering in mature en immature myeloide cellen (M1, M2, MDSC, DC).
o Bepalen van de shift in myeloide cel functie (IL-10 en IL-12 productie na LPS of anti-CD40 stimulatie).
o Bepalen van de verandering in stimulatie capaciteit APCs (MLR + cytokine productie na restimulatie).
• Serum voor start behandeling, dag van operatie en 7 dagen na laatste denosumab toediening:
o Bepalen van de verandering in RANKL, OPG met ELISA; TNF-alpha, IL-1-beta, IL-6, IL-7, IL-10, IL-15, IL-12, IFN gamma met luminex.
• Tumor
o Correleren van tumor (biopt en resectie materiaal), serum en PBMC immunologische parameters.
• Toxiciteit volgens NCI CTCAE v4.03.
• Bepalen van het beschrijvende verschil in event-vrije overleving na 3 jaar gebaseerd op immuun respons.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

• Postmenopausal, defined as 1 year without menstrual activity, previous bilateral oophorectomy, age older than 60 years or baseline FSH >20 U/l and estradiol <110 pmol/l.
• Clinical stage T1c + grade 3/4, stage II or III breast cancer amenable to adjuvant AC-T or ddAC-T combination chemotherapy.
• Measurable disease (breast and/or lymph nodes)
• Histological proven HER2-negative breast cancer in the core biopsy material.
• WHO 0-2
• Adequate bone marrow function (within 4 weeks prior to randomization): WBC≥3.0x10^9/l, neutrophils ≥1.5 x 10^9/l, platelets ≥100 x 10^9/l
• Adequate liver function (within 4 weeks prior to randomization): bilirubin ≤1.5 x upper limit of normal (UNL) range, ALAT and/or ASAT ≤2.5 x UNL, Alkaline Phosphatase ≤5 x UNL
• Adequate renal function (within 4 weeks prior to randomization): the calculated creatinine clearance should be ≥50 ml/min
• Albumin-adjusted serum calcium > 2.0 mmol/L (8.0mg/dL)
• Accessible for treatment and follow-up
• Written informed consent

• Postmenopauzaal, gedefinieerd als 1 jaar zonder menstruatie, eerdere bilaterale ovariectomie, leeftijd ouder dan 60 jaar of baseline FSH >20 U/l en oestradiol <110 pmol/l.
• Klinisch stadium T1c + graad 3/4, stadium II of III borstkanker in aanmerking komend voor adjuvante AC-T of ddAC-T combinatie chemotherapie.
• Meetbare ziekte (borst en/of lymfklieren)
• Histologisch bewezen HER2 negatieve borstkanker in het core biopsie materiaal.
• WHO 0-2
• Adequate beenmergfunctie (binnen 4 weken voor randomisatie): leukocyten ≥3.0 x 10^9/l, neutrofielen ≥1.5 x 10^9/l, bloedplaatjes ≥100 x 10^9/l
• Adequate leverfunctie (binnen 4 weken voor randomisatie): bilirubine ≤1.5 x bovenste limiet van normaal range, ALAT en/of ASAT ≤2.5 x bovenste limiet van normaal, Alkalische Fosfatase ≤5 x bovenste limiet van normaal.
• Adequate nierfunctie (binnen 4 weken voor randomisatie): de berekende kreatinine klaring moet ≥50 mL/min zijn
• Voor albumine gecorrigeerd serum calcium > 2.0mmol/L (8.0mg/dL)
• Patiënten moeten beschikbaar zijn voor behandeling en follow-up
• Geschreven informed consent

E.4

Principal exclusion criteria

• Evidence of distant metastases (M1)
• History of invasive breast cancer
• Prior chemotherapy or radiation therapy
• Previous malignancy within 5 years, with exception of a history of a previous basal cell carcinoma of the skin or pre-invasive carcinoma of the cervix.
• Serious other diseases as recent (last 6 months) myocardial infarction, clinical signs of cardiac failure or clinically significant arrhythmias.
• Prior or current bisphosphonate or denosumab usage.
• Osteoporosis as demonstrated on dexa vfa scan, defined as T ≤ 2.5 and/or a vertebral fracture.
• Current active dental problems including dental abscess or infection of the jawbone (maxilla or mandible), non-healed dental or oral surgery, a current or prior diagnosis of osteonecrosis of the jaw or planned invasive dental procedures for the course of the study.
• Known hypersensitivity reaction to any of the components of the treatment
• Medical or psychological condition which in the opinion of the investigator would not permit the patient to complete the study or sign meaningful informed consent

• Bewijs voor metastasen op afstand (M1)
• Invasieve borstkanker in de voorgeschiedenis
• Eerdere behandeling met chemotherapie of radiotherapie
• Maligniteit in de afgelopen 5 jaar, met uitzondering van een basaalcelcarcinoom van de huid of pre-invasief carcinoom van de cervix.
• Ernstige andere ziektes zoals een recent (laatste 6 maanden) myocard infarct, klinische tekenen van hartfalen, klinisch significante arrhytmieën.
• Eerder of huidig gebruik van bisfosfonaten of denosumab.
• Osteoporose aangetoond op dexa vfa scan, gedefinieerd als T ≤ 2.5 en/of vertebrale fractuur.
• Recente actieve tandheelkundige problemen inclusief tandheelkundige abcessen of infectie van het kaakbot (maxilla of mandibula), niet-genezen tandheelkundige of orale operaties, een recente of eerdere diagnose van osteonecrose van de kaak of geplande invasieve tandheelkundige procedures tijdens de duur van de studie.
• Bekende overgevoeligheid voor één van de bestanddelen van de behandeling
• Een medische of psychologische conditie die, zoals ingeschat door de onderzoeker, er toe zou leiden dat de patiënt niet tot het einde van de studie kan participeren of een betekenisvolle informed consent kan geven.

E.5 End points

E.5.1

Primary end point(s)

Change in intratumoral T-cell (CD4, CD8 and Treg) and Myeloid cell (M1/M2 Macrophage, MDSC, DC) numbers and function between the baseline biopsy and the surgical specimen.

Verandering in intratumorale T-cel (CD4, CD8 en Treg) en Myeloide cel (M1/M2 Macrofaag, MDSC, DC) aantallen en functie tussen het baseline biopt en chirurgisch specimen.

E.5.1.1

Timepoint(s) of evaluation of this end point

At time of operation.

Ten tijde van de operatie.

E.5.2

Secondary end point(s)

• PBMC before start treatment (t=1), at day of surgery before surgery (t=2) and 7 days after last denosumab administration (t=3):
o Shift in activated T effector cell levels (Ki67, HLA-DR, CD45RO, CD25, CD69, PD-1, TIM-3 and NKG-2A);
o Shift in regulatory T-cell levels (CD3, CD4, CD25, CD127, CD45RA, Foxp3, helios, CTLA-4 and Ki67);
o Change in functional response of T-cells (stimulation with recall antigens).
o Change in mature and immature myeloid cells (M1, M2,MDSC, DC).
o Shift in myeloid cell function (IL-10 and IL-12 production after LPS or anti-CD40 triggering).
o Change in stimulation capacity APCs (MLR + cytokine production after restimulation).
• Serum before start treatment (t=1), at day of surgery before surgery (t=2) and 7 days after last denosumab administration (t=3):
o Change in serum levels for RANKL, OPG by ELISA; TNF-alpha, IL-1-beta, IL-6, IL-7,IL-10, IL-15, IL-12, IFN gamma by luminex.
• Tumor:
o Correlation of tumor (biopsy and resection material) (intratumoral T-cell and Myeloid cell numbers), serum cytokine levels and PBMC immunologic parameters.
• Toxicity according to NCI CTCAE v4.03.
• Difference in descriptive event-free survival (EFS) at 3 year based on immune response.

• PBMC voor start behandeling (t=1), dag van operatie (t=2) en 7 dagen na laatste denosumab toediening (t=3):
o Shift in geactiveerde T effector cel levels (Ki67, HLA-DR, CD45RO, CD25, CD69, PD-1, TIM-3 and NKG-2A);
o Shift in regulatoire T cel levels (CD3, CD4, CD25, CD127, CD45RA, Foxp3, helios, CTLA-4 and Ki67);
o Verandering in functionele respons van T cellen (stimulatie met recall antigenen).
o Verandering in mature en immature myeloide cellen (M1, M2, MDSC, DC).
o Shift in myeloide cel functie (IL-10 en IL-12 productie na LPS of anti-CD40 stimulatie).
o Verandering in stimulatie capaciteit APCs (MLR + cytokine productie na restimulatie).
• Serum voor start behandeling (t=1), dag van operatie (t=2) en 7 dagen na laatste denosumab toediening (t=3):
o Verandering in serum levels van RANKL, OPG met ELISA; TNF-alpha, IL-1-beta, IL-6, IL-7, IL-10, IL-15, IL-12, IFN gamma met luminex.
• Tumor:
o Correleren van tumor (biopt en resectie materiaal), serum en PBMC immunologische parameters.
• Toxiciteit volgens NCI CTCAE v4.03.
• Verschil in beschrijvende event-vrije overleving na 3 jaar gebaseerd op immuun respons.

E.5.2.1

Timepoint(s) of evaluation of this end point

• Before start treatment (t=1), at day of surgery before surgery (t=2) and 7 days after last denosumab administration (t=3)
• Before start treatment (t=1), at day of surgery before surgery (t=2) and 7 days after last denosumab administration (t=3)
• Tumor: baseline and surgery. Serum/PBMC: t=1, t=2, t=3
• From start till end of therapy + until 30 days after completion of the therapy.
• At 3 years after randomization

• Voor start behandeling (t=1), dag van operatie (t=2) en 7 dagen na laatste denosumab toediening (t=3)
• Voor start behandeling (t=1), dag van operatie (t=2) en 7 dagen na laatste denosumab toediening (t=3)
• Tumor: baseline en chirurgie. Serum/PBMC: t=1, t=2, t=3
• Vanaf begin tot einde therapie + tot 30 dagen vanaf het staken van de therapie.
• Na 3 jaar na randomizatie

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

E.6.5

Efficacy

E.6.6

Pharmacokinetic

E.6.7

Pharmacodynamic

Yes

E.6.8

Bioequivalence

E.6.9

Dose response

Yes

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)

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

Yes

E.8.1.1

Randomised

Yes

E.8.1.2

Open

Yes

E.8.1.3

Single blind

E.8.1.4

Double blind

E.8.1.5

Parallel group

Yes

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

Yes

E.8.2.3.1

Comparator description

Geen denosumab.

No denosumab.

E.8.2.4

Number of treatment arms in the trial

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

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

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)

F.1.1.6

Adolescents (12-17 years)

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

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.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.

Geen.

G. Investigator Networks to be involved in the Trial
G.4 Investigator Network to be involved in the Trial: 1
G.4.1	Name of Organisation	Dutch Breast Cancer Research Group (BOOG)
G.4.3.4	Network Country	Netherlands
G.4 Investigator Network to be involved in the Trial: 2
G.4.1	Name of Organisation	Patient Advocacy Group (PAG)
G.4.3.4	Network Country	Netherlands

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

Competent Authority Decision

Authorised

Date of Competent Authority Decision

2017-12-21

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2018-04-25

P. End of Trial
P.	End of Trial Status	Prematurely Ended
P.	Date of the global end of the trial	2018-10-11

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