Clinical Trials Register

Summary
EudraCT Number:	2012-004046-15
Sponsor's Protocol Code Number:	TKA4
National Competent Authority:	Denmark - DHMA
Clinical Trial Type:	EEA CTA
Trial Status:	Ongoing
Date on which this record was first entered in the EudraCT database:	2013-07-03
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

Denmark - DHMA

A.2

EudraCT number

2012-004046-15

A.3

Full title of the trial

A 4-way randomized double-blinded migration (RSA), bone density (DXA), and biomarker study assessing adaptive bone changes and implant fixation and longevity of the new Regenerex Porous Titanium Tibial Tray with different adjuvant medical therapies.

A.3.1

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

Can treatment with drugs developed to treat thin and weakened osteoporotic bones make knee implants stay fixed in the bones and last longer?

A.4.1

Sponsor's protocol code number

TKA4

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	ORtopædkirurgisk Forskningsenhed, Aarhus Universitetshospital
B.1.3.4	Country	Denmark
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	Biomet Europe
B.4.2	Country	Denmark
B.4.1	Name of organisation providing support	Det Frie Forskningsråd
B.4.2	Country	Denmark
B.4.1	Name of organisation providing support	Gigtforeningen
B.4.2	Country	Denmark
B.4.1	Name of organisation providing support	Sahva (Bevica) Fonden
B.4.2	Country	Denmark
B.4.1	Name of organisation providing support	Beckett Fonden
B.4.2	Country	Denmark
B.4.1	Name of organisation providing support	Fonden til lægevidenskabens fremme (AP Møller)
B.4.2	Country	Denmark
B.4.1	Name of organisation providing support	Aase & Ejner Danielsens Fond
B.4.2	Country	Denmark
B.4.1	Name of organisation providing support	Klinisk Institut, Aarhus Universitet
B.4.2	Country	Denmark
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Ortopædkirurgisk Forskningsenhed
B.5.2	Functional name of contact point	Maiken Stilling
B.5.3	Address:
B.5.3.1	Street Address	Tage-Hansens Gade 2
B.5.3.2	Town/ city	Aarhus C
B.5.3.3	Post code	8000
B.5.3.4	Country	Denmark
B.5.4	Telephone number	004578467471
B.5.6	E-mail	ortoforsk@ki.au.dk

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	Zoledronic Acid (Zoledronsyre)
D.2.1.1.2	Name of the Marketing Authorisation holder	Actavis A/S
D.2.1.2	Country which granted the Marketing Authorisation	Denmark
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	Solution for infusion
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Topical use (Noncurrent) Intraosseous use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	ZOLEDRONIC ACID MONOHYDRATE
D.3.9.1	CAS number	165800-06-6
D.3.9.3	Other descriptive name	ZOLEDRONIC ACID MONOHYDRATE
D.3.9.4	EV Substance Code	SUB21645
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	0.8
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	Prolia
D.2.1.1.2	Name of the Marketing Authorisation holder	Amgen Eurpoe B.V.
D.2.1.2	Country which granted the Marketing Authorisation	Denmark
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	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	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	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

Osteoarthritis in the knee treated with cementless total knee arthroplasty

Sligigt i knæleddet der behandles med ucementeret knæledsprotese

E.1.1.1

Medical condition in easily understood language

Osteoarthritis in the knee treated with cementless total knee arthroplasty

Sligigt i knæleddet der behandles med ucementeret knæledsprotese

E.1.1.2

Therapeutic area

Diseases [C] - Musculoskeletal Diseases [C05]

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	16.1
E.1.2	Level	LLT
E.1.2	Classification code	10023476
E.1.2	Term	Knee osteoarthritis
E.1.2	System Organ Class	100000004859

E.1.3

Condition being studied is a rare disease

E.2 Objective of the trial

E.2.1

Main objective of the trial

Investigate the possibility to improve immediate and long term fixation of cementless tibial components of total knee arthroplasty by use of adjuvant treatment by denosumab or topical zoledronic acid through assessment of implant migration in relation to the bone by radiostereophotogrammetric analysis (RSA) and assessment of bone mineral density changes in the periprosthetic bone as measured by dual energy x-ray absorptiometry (DXA).

H1: Tibial components are more stable (RSA) in the intervention groups receiving active substances (denosumab s.c. injection or topical zoledronic acid) compared to placebo.

E.2.2

Secondary objectives of the trial

H2: The periprostetic bone is better conserved in proximity of tibial components when adjuvant treatment by denosumab or zoledronic acid is used as compared to placebo.
H3: Adjuvant treatment by denusomab will result in a systemic response whereas treatment with topical zoledronic acid and placebo will not result in a systemic response as measured by bone formation markers.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

- primary knee osteoarthritis in capable men and women
- sufficient bone quality for total cruxiate retaining knee arthroplasty
- age above 18 years but maximum 75 years of age
- informed and written consent

E.4

Principal exclusion criteria

- neuromuscular or vascular disease in the affected leg
- peroperatively found to be unsuitable for a primary knee arthroplasty
- osteoporosis based on former diagnosis or preoperative DXA-scan
- fracture sequelae or previous PTO or previous extensive knee surgery
- need for a stem-elongation
- NSAID postoperatively
- pregnancy (positive pregnancy test) or at risk of becoming pregnant during the project (not using safe anti-conceptive agents like contraceptive pills, intra-uterine device (IUD), hormone depot injection, subdermal implantation of a contraceptive rod, hormone vaginal ring, transdermal depot hormone sticking plaster)
- metabolic bone disease
- rheumatoid arthritis
- renal failure (GFR < 30 ml/min)
- persistent hypocalcaemia
- allergic to bisphosphonate or denusomab
- sporadic or permanent need of systemic glucocorticoid treatment
- active cancer
- radiation or chemotherapy
- poor dental status (increased risk of jaw-necrosis with bisphosphonates/denusomab)
- high use of alcoholic beverages (women > 14, men > 21 units/week)

E.5 End points

E.5.1

Primary end point(s)

Implant migration (RSA) measured continuously from baseline to follow-up (MTPM) and estimation of Continuous MTPM (MTPM migration > 0.2 mm between 12 and 24 months of follow-up) according to Ryd et al. (Ryd et al., 1995).

E.5.1.1

Timepoint(s) of evaluation of this end point

First patient, first visit June 2013.
Last Patient, last visit November 2025.

E.5.2

Secondary end point(s)

DXA - Changes in Bone Mineral Density under the Tibial Tray and in proximity of the central stem.

Biomarkers - Bone resorption from baseline to follow-ups and correlation between bone density changes, biomarkers of bone resorption and implant migration

E.5.2.1

Timepoint(s) of evaluation of this end point

First patient, first visit June 2013.
Last Patient, last visit November 2025.

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

E.6.5

Efficacy

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

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

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)

Yes

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

When a total of 100 patients have been included and operated, and trial treatment and 10 years follow-up have been completed.

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

100

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)

Subjects will be followed for 10 years during the trial. Thereafter if any complications have occured the subjects will be treated according to current standards and followed at Aarhus University Hospital.

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

2013-07-03

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2012-10-24

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

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