Clinical Trials Register

Summary
EudraCT Number:	2018-000552-18
Sponsor's Protocol Code Number:	1155/2018
National Competent Authority:	Austria - BASG
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2019-10-18
Trial results	View 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

Austria - BASG

A.2

EudraCT number

2018-000552-18

A.3

Full title of the trial

Denosumab in the prevention of immobilization-induced bone loss in Intensive Care Unit patients

Denosumab in der Prävention des Knochenabbaus immobilisierter Patienten auf einer Intensivstation

A.3.1

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

Denosumab in the prevention of immobilization-induced bone loss in Intensive Care Unit patients

Denosumab in der Vorbeugung des immobilisations-bedignten Knochenabbaus intensivpflichtiger Patienten

A.4.1

Sponsor's protocol code number

1155/2018

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	Medical University of Vienna
B.1.3.4	Country	Austria
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 University of Vienna
B.4.2	Country	Austria
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Medical University of Vienna
B.5.2	Functional name of contact point	Clincial Trial Information Desk
B.5.3	Address:
B.5.3.1	Street Address	Waehrigner Guertel 18-20
B.5.3.2	Town/ city	Vienna
B.5.3.3	Post code	1090
B.5.3.4	Country	Austria
B.5.4	Telephone number	004314040043330
B.5.5	Fax number	004314040052810
B.5.6	E-mail	pmr-office@meduniwien.ac.at

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	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	Solution for 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	Immunoglobulin G2 Human Monoclonal Antibody to RANK Ligand
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	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
D.8 Placebo: 1
D.8.1	Is a Placebo used in this Trial?	Yes
D.8.3	Pharmaceutical form of the placebo	Solution for injection/infusion
D.8.4	Route of administration of the placebo	Subcutaneous use

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

Immobilization because of aneurysmal subarachnoidal haemorrhage (aSAH) with moderate-severe neurological deficits (e.g. hemiparesis) and reduced state of consciousness – equivalent to Hunt&Hess 4-5 – at the time of admission to ICU

Immobilisation aufgrund einer aneurysmatischen Subarachnoidalblutung mit moderaten bis schweren neurologischen Defiziten (z.B.Hemiparese) aud reduziertem Bewusstsein – äquivalent Hunt&Hess 4-5 – zum Zeitpunkt der Aufnahme auf die Intensivstation

E.1.1.1

Medical condition in easily understood language

Immobilization because of reduced consciousness and neurological deficits because of an intracranial bleeding

Immobilisation aufgrund von Bewusstseineintrübung und neurologischen Ausfällen bedingt durch eine Hirnblutung

E.1.1.2

Therapeutic area

Diseases [C] - Musculoskeletal Diseases [C05]

MedDRA Classification

E.1.3

Condition being studied is a rare disease

E.2 Objective of the trial

E.2.1

Main objective of the trial

twofold:
a) to evaluate if a single administration of denosumab decreases bone resorption (CTX-1) within one month in immobilized patients
b) to evaluate if one year of denosumab therapy has a positive effect on the immobilization-associated bone loss. (hip region) Additionally, potential changes of BTMs will be evaluated.

Pilot study (n=14):
evaluate if a single administration of denosumab decreases bone resorption (CTX-1) within one month in immobilized patients

zweifach:
a) Änderung des Serumspiegles von CTX-1 zwischen Baseline und 1 Monat nach erster Denosumab-Gabe
b) Änderung der Knochenmineraldichte der Hüftregion ein Jahr nach erster Denosumab-Gabe

Pilotstudie (n=14):
Änderung des Serumspiegles von CTX-1 zwischen Baseline und 1 Monat nach Denosumab-Gabe

E.2.2

Secondary objectives of the trial

a) Serum levels of osteocalcin (Oc), bone-spcific alkaline Phosphatase (BAP), procollagen ta) pe 1 amino-terminal propeptide (P1NP), Tartate resistante acid phosphatase (TRAP), dickkopf 1 (DKK1), sclerostin (SOST), periostin (PSTN), 24-h urine: Ca excretion one month and twelve months after 1st denosumab application
b) BMD: T-score lumbar spine twelve months after 1st denosumab application
c) Reasons for drop outs

Pilot study (n=14):
cortical thickness and density index of the proximal tibia (quantitative ultrasound) - characterization of subjects

a) Serum piegel von Osteokalzin (Oc), knochen-spezifischer alkalischer Phosphatase (BAP), Prokollagen Typ 1 amino-terminales Propeptid (P1NP), Tartat resistente sauere Phosphatase (TRAP), Dickkopf 1 (DKK1), Sklerostin (SOST), Periostin (PSTN), 24-h Harn: Ca Ausscheidung ein Monat und 12 Monate nach erster Denosumab-Gabe
b) KMD: T-Score der LWS 12 Monate nach erster Denosumab-Gabe
c) Gründe für Studienabbruch

Pilotstudie (n=14):
Kortikale Dicke und Dichteindex an der proximalen Tibia (Quantitative Ultraschallmessung) - zur Charakterisierung des Kollektivs

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

Women, men
30-80 years of age
Patients after aneurysmal subarachnoidal haemorrhage (aSAH) with moderate-severe neurological deficits (e.g. hemiparesis) and reduced state of consciousness – equivalent to Hunt&Hess 4-5 – at the time of admission to ICU
Normal liver function

Frauen und Männer
30-80 Jahre
Patienten, die aufgrund einer Hirnblutung bei Aufnahme auf der Intensivstation moderate bis schwere neurologische Defizite und eine eingeschränkte Bewusstseinslage haben (Hunt&Hess 4-5)
Normale Leberfunktion

E.4

Principal exclusion criteria

Patients after aneurysmal subarachnoidal haemorrhage (aSAH; Hunt&Hess 0-3)
Patients after intracerebral bleeding
Subjects with a history of prior solid organ transplantation
Cancer within the previous 5 years
Pregnancy
Rheumatoid arthritis
Severe renal insufficiency (CKD V)
Intake of drugs with potential effects on BMD like lithium, estrogen-replacement therapy, selective estrogen-receptor modulators (SERMS), oral bisphosphonates in the last three months, denosumab and parenteral bisphosphonates in the last year - except medication necessary for the underlying disease
Non-osteoporotic bone disease
Recent fragility fracture within 6 months

Patienten nach aneurysmatischer Subarachnoidalblutung (aSAH; Hunt&Hess 0-3)
Patients nach intrazerebraler Blutung
Personen nach solider Organtransplantation
Malignom innerhalb der letzten 5 Jahre
Schwangerschaft
Rheumatoide Arthritis
Schwere Niereninsuffizienz(CKD V)
Einnahme von Medikamenten mit potentiellem Effekt auf die Knochenmineraldichte wie Lithium, Hormonersatztherapie, Selektive Östrogen-Rezeptor Modulatoren (SERMS), orale Bisphosphonate in vergangenen 3 Monaten, Denosumab und parenterale Bisphosphonates im vergangeen Jahr - ausgenommen Medikation welche aufgrund der Grunderkrankung nötig ist
Nicht-osteoporotische Knochenerkrankung
Fragilitätsfraktur innerhalb der letzten 6 Monate

E.5 End points

E.5.1

Primary end point(s)

a) Serum levels of carboxy-terminal collagen crosslinks (CTX-1) one month after first denosumab application
b) BMD of the hip region one year after the first denosumab application

Pilot study (n=14):
Serum levels of carboxy-terminal collagen crosslinks (CTX-1) one month after denosumab application

a) Serumspiegel von Carboxy-terminalen Kollagen Crosslinks (CTX-1) ein Monat nach erster Denosumab-Gabe
b) KMD der Hüftregion of the hip region ein Jahr nach erster Denosumab-Gabe

Pilotstudie (n=14):
Serumspiegel von Carboxy-terminalen Kollagen Crosslinks (CTX-1) ein Monat nach Denosumab-Gabe

E.5.1.1

Timepoint(s) of evaluation of this end point

a) CTX-1: before first denosumab application, one month after first denosumab application
b) BMD: one month and 12 months after first denosumab application

Pilot study (n=14):
cortical thickness and density index of the proximal tibia (quantitative ultrasound): within one week after baseline

a) CTX-1: vor erster Denosumab-Gabe, ein Monat nach erster Denosumab-Gabe
b) KMD: ein Monat und 12 Monate nach erster Denosumab-Gabe

Pilotstudie (n=14):
CTX-1: vor Denosumab-Gabe, ein Monat nach Denosumab-Gabe

E.5.2

Secondary end point(s)

a) Serum levels of osteocalcin (Oc), bone-spcific alkaline Phosphatase (BAP), procollagen type 1 amino-terminal propeptide (P1NP), Tartate resistante acid phosphatase (TRAP), dickkopf 1 (DKK1), sclerostin (SOST), periostin (PSTN), 24-h urine: Ca excretion one month and twelve months after 1st denosumab application
b) BMD: T-score lumbar spine twelve months after 1st denosumab application
c) Reasons for drop outs

a) Serumspiegel von Osteokalzin (Oc), knochen-spezifischer alkalischer Phosphatase (BAP), Prokollagen Typ 1 amino-terminales Propeptid (P1NP), Tartat resistente sauere Phosphatase (TRAP), Dickkopf 1 (DKK1), Sklerostin (SOST), Periostin (PSTN), 24-h Harn: Ca Ausscheidung ein Monat und 12 Monate nach erster Denosumab-Gabe
b) KMD: T-Score der LWS 12 Monate nach erster Denosumab-Gabe
c) Gründe für Studienabbruch

Pilotstudie (n=14):
Kortikale Dicke und Dichteindex an der proximalen Tibia (Quantitative Ultraschallmessung) - innerhalb einer Woche nach Baseline

E.5.2.1

Timepoint(s) of evaluation of this end point

Biochemical parameters: before first denosumab application, one month, 6 and 12 months after first denosumab application
BMD: one month and 12 months after first denosumab application
Reasons for drop outs: on occasion

Laborparameter: vor erster Denosumab-Gabe, ein Monat, 6 und 12 Monate nach erster Denosumab-Gabe
KMD: ein Monat und 12 Monate nach erster Denosumab-Gabe
Gründe für Studienabbruch: anlassbezogen

E.6 and E.7 Scope of the trial

E.6

Scope of the trial

E.6.1

Diagnosis

E.6.2

Prophylaxis

Yes

E.6.3

Therapy

E.6.4

Safety

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)

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

Yes

E.8.1.1

Randomised

Yes

E.8.1.2

Open

E.8.1.3

Single blind

E.8.1.4

Double blind

Yes

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

Yes

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

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 For clinical trials recorded in the database before the 10th March 2011 this question read: "Women of childbearing potential" and did not include the words "not using contraception". An answer of yes could have included women of child bearing potential whether or not they would be using contraception. The answer should therefore be understood in that context. This trial was recorded in the database on 2019-10-18.

Yes

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

Yes

F.3.3.6

Subjects incapable of giving consent personally

Yes

F.3.3.6.1

Details of subjects incapable of giving consent

Patients with reduced state of conciousness after aneurysmal subarachnoidal haemorrhage

Patienten mit reduzierter Bewusstseinslage nach Subarachnoidalblutung

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

Keine

G. Investigator Networks to be involved in the Trial
G.4 Investigator Network to be involved in the Trial: 1

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

Competent Authority Decision

Authorised

Date of Competent Authority Decision

2019-12-06

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2018-09-25

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2022-05-31

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