Clinical Trials Register

Summary
EudraCT Number:	2016-003300-31
Sponsor's Protocol Code Number:	20159460(c)
National Competent Authority:	Greece - EOF
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2017-03-28
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

Greece - EOF

A.2

EudraCT number

2016-003300-31

A.3

Full title of the trial

Evaluation of the efficacy of Denosumab in adult patients with Langerhans Cell Histiocytosis (LCH) : a multiple-site, single arm, open label Clinical Trial.

ΑΞΙΟΛΟΓΗΣΗ ΤΗΣ ΕΠΙΔΡΑΣΗΣ ΤΗΣ ΔΕΝΟΣΟΥΜΑΜΠΗΣ ΣΕ ΕΝΗΛΙΚΕΣ ΑΣΘΕΝΕΙΣ ΜΕ ΙΣΤΙΟΚΥΤΤΩΣΗ ΕΚ ΚΥΤΤΑΡΩΝ LANGERHANS (LCH): ΜΙΑ ΠΟΛΥΚΕΝΤΡΙΚΗ, ΕΝΟΣ ΣΚΕΛΟΥΣ, ΑΝΟΙΧΤΟΥ ΣΧΕΔΙΑΣΜΟΥ ΚΛΙΝΙΚΗ ΜΕΛΕΤΗ

A.3.1

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

A study for the assessment of therapeutic efficacy of a drug (Denosumab) that will be administered in adult patients with mild symptoms of LCH.

Μελέτη για την εκτίμηση της θεραπευτικής αποτελεσματικότητας ενός φαρμακου (Δενοσουμάμπη) το οποίο θα χορηγηθεί σε ενήλικες ασθενείς με ήπια συμπτώματα LCH.

A.4.1

Sponsor's protocol code number

20159460(c)

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	Hellenic Society for the Study of Bone Metabolism
B.1.3.4	Country	Greece
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	Hellenic Society for the Study of Bone Metabolis
B.4.2	Country	Greece
B.4.1	Name of organisation providing support	Amgen Europe B.V.
B.4.2	Country	European Union
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	CORONIS Research S.A
B.5.2	Functional name of contact point	Charalampos Therianos
B.5.3	Address:
B.5.3.1	Street Address	Nikitara 2
B.5.3.2	Town/ city	Chalandri
B.5.3.3	Post code	15232
B.5.3.4	Country	Greece
B.5.4	Telephone number	+302108778000
B.5.5	Fax number	+302108778202
B.5.6	E-mail	htherianos@coronis.gr

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	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	European Union
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	denosumab
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.3.9.4	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	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	Yes
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

Langerhans Cell Histiocytosis (LCH) is a rare disease of unknown etiology with variable clinical course exhibiting both neoplastic and inflammatory features. It is characterized by the accumulation and/or proliferation of specific dendritic cells resembling normal epidermal Langerhans cells.

E.1.1.1

Medical condition in easily understood language

Adult patients with mild symptoms of Langerhans Cell Hystiocytosis

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	21.1
E.1.2	Level	PT
E.1.2	Classification code	10069698
E.1.2	Term	Langerhans' cell histiocytosis
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

Yes

E.2 Objective of the trial

E.2.1

Main objective of the trial

The primary study objective is to assess the therapeutic efficacy of denosumab 120 mg, administered sc every 8 weeks (Q8W) in adult LCH patients.

E.2.2

Secondary objectives of the trial

1) To define an uniform treatment approach for LCH patients with mild symptoms and low risk disease.
2) To explore the efficacy of denosumab 120 mg Q8W sc in reducing disease reactivations after treatment completion.
3) To illustrate the safety profile of denosumab in LCH patients.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1)Adults (>18 years of age)

2)Definitive diagnosis of LCH [1] [Based on clinic-pathological evidence with microscopic examination and at least one of the following immunological staining: Langerin (CD 207) positivity, CD1a positivity, Presence of Birbeck granules on electronic microscopy]

3)Mild symptoms needing first line systemic therapy for LCH because of:

-single system disease with multifocal lesions;

-single system disease with “special site” lesions (vertebral lesions with intraspinal extension, craniofacial bone lesions with soft tissue extension);

-multi-system disease without involvement of risk organs (hematopoietic system, spleen, liver, tumorous CNS.).

4) Have signed the informed consent form (consent should be taken before any study-specific procedure is performed).

5) A patient should undergo a PET-CT imaging test, in order for him to be deemed suitable for the study. The initial PET-CT either may have been carried out, within 3 months prior to visit 1, regardless of the diagnostic center or the type of the device, which has been used for, or may take place in the context of visit 2, at the diagnostic center(s) specialized on Nuclear Medicine, which have been partnered with the Sponsor. Whichever is the case, the initial PET-CT report should be legible and accurate, so that to be assessed by the qualified physician, responsible for the PET-CT test at the partnered diagnostic center(s).

E.4

Principal exclusion criteria

1. Symptomatic multi system LCH - no risk organs involved.
2. Multi-system LCH (with or without symptoms) - risk organs involved.
3. Isolated pulmonary LCH disease
4. Previous administration of denosumab from clinical trials or other use (e.g. commercial use).
5. Current participation in another clinical trial or having received any investigational product within the last 3 months.
6. Impaired renal function as determined by an estimated glomerular filtration rate eGFR of ≤ 30 mL/min/1,73m2 [using the Chronic Kidney Disease-Epidemiology, (CKD-EPI) formula].
7. Patients that have received oral bisphosphonates within 6 months of study enrollment or intravenous bisphosphonates, fluoride and strontium ranelate within 1 year of study enrollment.
8. Treatment with immune suppressive agents within 4 weeks from baseline evaluation.
9. Patients with severe impairment of clinical condition including: severely impaired pulmonary function (for example TLC<60%, FEV1<30%, DLCO<30%, PaO2<55 mmHg), long term oxygen therapy or cor pulmonale.
10. Known to have a liver failure or chronic hepatic disease e.g. cirrhosis, chronic hepatitis; or elevated transaminases defined as ALT and/or AST > 2 fold the upper limit of normal laboratory range.
11. Heart failure (NYHA above 2).
12. Patients with life expectancy of less than one year.
13. Female subjects of childbearing potential who refuse to use a reliable contraceptive method throughout the study, defined as use of 2 highly effective forms of contraception and continuation of use for 7 months after last administration of study drug. Birth control methods that can achieve a failure rate of less than 1% per year, when used consistently and correctly, are considered as highly effective.
Highly effective methods of birth control include:
•Combined (estrogen and progestogen) hormonal methods (pills, vaginal ring, or skin patch)
•Single hormonal methods (progesterone) to stop release of the egg from the ovary (pills, shots/injections, or implants placed under the skin by a healthcare provider)
•Intrauterine device (IUD)
•Intrauterine hormonal-releasing system (IUS)
•Surgery to tie both fallopian tubes (bilateral tubal ligation/occlusion
•A male partner has had a vasectomy and testing shows there is no sperm in the semen
•Sexual abstinence (not having sex)
14. Pregnancy, planning a pregnancy or currently lactating
15. Severe concurrent illness which in the investigator’s opinion may confound patient evaluation, e.g. malignancy (except basal cell carcinoma, cervical or breast ductal carcinoma in situ) within the last 5 years.
16. Known alcohol or drug abuse.
17. PTH, PTH derivatives, teriparatide, odanacatib, anabolic steroids, testosterone, glucocorticosteroids (> 5 mg/day of prednisone equivalent for > 10 days), systemic hormone-replacement therapy, selective estrogen receptor modulators (SERMs), raloxifene, tibolone, calcitonin use within the last 6 weeks.
18. Evidence of hyper- or hypothyroidism; patients with an abnormal TSH level on thyroid treatment (patients on stable thyroid treatment with a normal TSH allowed); current hyper- or hypoparathyroidism; current hyper or hypocalcemia (hypercalcemia based on albumin adjusted serum calcium > 10.40 mg/dL; hypocalcemia based on albumin adjusted serum calcium < 8.5 mg/dL); vitamin D deficiency (25-hydroxy vitamin D level < 20 ng/mL; if the resulted value of the retest is 20 ≥ ng/Ml, after repletion with 50,000 – 100,000 IU of cholecalciferol, subject will be allowed. The retest should be carried out within 30 days post to visit 1(screening)); rheumatoid arthritis; Paget’s disease; any known bone disease with osteolytic and/or osteoblastic lesions that would interfere with interpretation of findings.
19. Known sensitivity to mammalian cells, denosumab or any components of denosumab 120mg, or any of the products to be administered during the study (e.g., calcium or vitamin D).
20. History of any Solid Organ or Bone Marrow Transplant.
21. History of osteonecrosis of the jaw, and/or recent tooth extraction or other dental surgery; or planned invasive dental work during the study.
22. Intolerance to calcium supplements.
23. Malabsorption syndrome; severe malabsorptin including Celiac disease, Short Bowel Syndrome, Crohn's disease, Previous Gastric Bypass.

E.5 End points

E.5.1

Primary end point(s)

The primary efficacy endpoint is defined as the percentage of patients with progression of disease.

E.5.1.1

Timepoint(s) of evaluation of this end point

Month 8

E.5.2

Secondary end point(s)

The secondary efficacy endpoints include the following:
- Reactivation-free survival.
- Percentage of patients with disease-related permanent sequelae (developed during the study).

Safety endpoints include the following:
- Incidence of Adverse Events during the trial.
- Changes from baseline in safety laboratory analytes (serum chemistry, hematology) and vital signs. In specific, the parameters of serum chemistry and haematology that are of particular interest include: CRP, ESR, Hemoglobin, White blood count and differential, SGOT, SGPT, urea, creatinine, and calcium.

E.5.2.1

Timepoint(s) of evaluation of this end point

month 18

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

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)

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

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

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

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

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)

- If patients still manifest symptoms of the disease, they will be treated with methotrexate and azathioprine

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

2017-06-13

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2017-05-26

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2022-06-22

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