Clinical Trials Register

Summary
EudraCT Number:	2006-003688-30
Sponsor's Protocol Code Number:	CSI-040101/02
National Competent Authority:	Spain - AEMPS
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2007-01-29
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

Spain - AEMPS

A.2

EudraCT number

2006-003688-30

A.3

Full title of the trial

A phase 2 randomized, controlled, open-label (dose-blinded), multi-center, dose-finding study of the safety and efficacy of I-0401 in the treatment of patients with fractures of the tibial plateau requiring grafting.

Estudio en fase 2 aleatorizado, controlado, abierto (ciego para la dosis), multicéntrico, de búsqueda de dosis de seguridad y eficacia de I-0401 en el tratamiento de pacientes con fractura de meseta tibial que requieran injerto

A.3.1

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

A scientific experiment to further test the safety and efficacy of I-0401 in the treatment of patients with fractures of the upper surface of the shin bone requiring transplant bone tissue (from their own). In several centers, study subjects are randomly allocated to receive one or other of the alternative treatments under study, without being aware of the concentration received.

A.4.1

Sponsor's protocol code number

CSI-040101/02

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	Kuros Biosurgery AG
B.1.3.4	Country	Switzerland
B.3.1 and B.3.2	Status of the sponsor	Commercial
B.4 Source(s) of Monetary or Material Support for the clinical trial:
B.4.1	Name of organisation providing support	Baxter Healthcare Corp.
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	Kuros Biosurgery AG
B.5.2	Functional name of contact point	Chief Medical Officer
B.5.3	Address:
B.5.3.1	Street Address	Technoparkstrasse 1
B.5.3.2	Town/ city	Zürich
B.5.3.3	Post code	8005
B.5.3.4	Country	Switzerland
B.5.4	Telephone number	+41442005600
B.5.5	Fax number	+41442005700
B.5.6	E-mail	info@kuros.ch

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	No
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	TGplPTH1-34 in fibrin supplemented with hydroxyapatite/beta tricalcium phosphate granules
D.3.2	Product code	I-0401
D.3.4	Pharmaceutical form	Implant
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Intraosseous use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.9.2	Current sponsor code	Kuros PTH1-34
D.3.9.3	Other descriptive name	TGplPTH1-34
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	0.4
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)	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	Yes
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	Yes
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	No
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	TGplPTH1-34 in fibrin supplemented with hydroxyapatite/beta tricalcium phosphate granules
D.3.2	Product code	I-0401
D.3.4	Pharmaceutical form	Implant
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Intraosseous use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.9.2	Current sponsor code	Kuros PTH1-34
D.3.9.3	Other descriptive name	TGplPTH1-34
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	1.0
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)	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	Yes
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	Yes
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

Fractures of the tibial plateau requiring grafting

Fracturas de meseta tibial que requieran injerto

E.1.1.1

Medical condition in easily understood language

Fractures of the upper surface of the shin bone requiring transplant bone tissue (from their own)

E.1.1.2

Therapeutic area

Analytical, Diagnostic and Therapeutic Techniques and Equipment [E] - Surgical Procedures, Operative [E04]

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	14.0
E.1.2	Level	HLT
E.1.2	Classification code	10024956
E.1.2	Term	Lower limb fractures
E.1.2	System Organ Class	10028395 - Musculoskeletal and connective tissue disorders

E.1.3

Condition being studied is a rare disease

E.2 Objective of the trial

E.2.1

Main objective of the trial

To assess the effects of a single implant of I-0401 (2 different concentrations) given in addition to internal fixation in tibia plateau fractures requiring grafting

E.2.2

Secondary objectives of the trial

- To assess the tolerability and safety of I-0401
- To assess pharmacokinetics of PTH
- To assess quality of life and pharmacoeconomics

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1. Radiological evidence of fracture of the tibial plateau requiring grafting and fixation that occurs either alone or is part of a polytraumatic event (AO classification: 41B2, 41B3, 41C2, 41C3).
2. Female and male subjects ≥ 18 years.
3. Body mass index (BMI) 16-33 (minimum body weight 50 kg, maximum 140 kg).
4. Glasgow coma score (GCS) ≥ 13.
5. Females of child-bearing potential must be willing to undergo a pregnancy test (urine) prior to treatment start (at screening).
6. Females of child-bearing potential randomized in the intervention group must agree to have acceptable contraception for at least 3 months after receiving I 0401.
7. Subjects must be able and willing to come to the clinic for follow up visits as scheduled in the time and events schedule.
8. Signed Informed Consent Form (ICF). The patient has to be able to give consent personally.

E.4

Principal exclusion criteria

1. Total size of defect requiring a graft volume of > 7.0 mL.
2. Patients with high risk of amputation.
3. Open tibial plateau fractures Gustilo-Anderson grade III.
4. Concomitant ipsilateral fractures of the limb other than the fracture of the tibial plateau.
5. Active or past history of malignant tumor.
6. Evidence of systemic or localized infection at time of surgery.
7. Pregnant or lactating females.
8. Evidence of immune-suppression.
9. On treatment and/or planned treatment with products containing PTH (e.g. Forteo®, Forsteo®).
10. Evidence of hypercalcemia (serum calcium above ULN).
11. Known history of allergy to anesthetics.
12. Suspected or known allergies towards any of the components of I-0401 (TGplPTH1-34, Fibrin, HA/TCP granules).
13. History or evidence for a metabolic bone disease other than primary osteoporosis.
14. Known clinically significant organ or systemic diseases or any other relevant medical condition such that in the opinion of the investigator, the significance of the disease or condition will impose hazard to the patient if study therapy will be initiated or will compromise the subject’s participation in the study.
15. Participation in another clinical trial within 3 months prior to trial start.
16. Evidence of moderate or severe renal failure (serum creatinine > 3.0 times ULN, NCI CTC grades 3 and 4).
17. History of allergic thrombocytopenia (type II) induced by heparin.
18. Inexplicable elevations of alkaline phosphatase (alkaline phosphatase > 5.0 times ULN, NCI CTC grades 3 and 4).
19. Prior external beam or implant radiation therapy to the skeleton.

E.5 End points

E.5.1

Primary end point(s)

The proportion of patients with radiological fracture union at 16 weeks after implantation of the graft. Assessments will be performed by an independent radiological panel and will be based on CTs. Radiological fracture union will be defined using the following criteria:
- Cortical bridging on at least 1 visible cortical plane and
- Obliteration of fracture lines and
- Dislocation of bone fragments compared to the post-operative film.

E.5.1.1

Timepoint(s) of evaluation of this end point

16 weeks

E.5.2

Secondary end point(s)

• Loss of reduction of the tibia plateau (in mm) at 6, 12, 16, 26, 52 and 104 weeks after surgery compared to the post-operative assessment as measured by an independent radiological panel.
• The proportion of patients with radiological fracture union at 52 and 104 weeks as assessed by an independent radiological panel.
• Proportion of patients with fracture healing at 16 weeks after implantation of the graft as assessed by the investigators considering clinical and radiological criteria. Clinical assessment will consider the level of pain upon weight bearing on fracture site, the level of redness/swelling of the knee and whether a secondary intervention was necessary to promote fracture healing. Radiological criteria will consider cortical bridging and fracture lines.
• Time to fracture healing as assessed by the investigators considering clinical and radiological criteria (see above for fracture healing assessment). • The number of secondary interventions due to non-healing within 52 weeks and within 104 weeks from time of surgery comprises:
o All surgical procedures to promote fracture-healing. o All surgical procedures to perform a knee arthroplasty
o Non-invasive treatments (e.g. ultrasound) to promote fracture- healing.

E.5.2.1

Timepoint(s) of evaluation of this end point

• Loss of reduction of the tibia plateau (in mm) at 6, 12, 16, 26, 52 and 104 weeks after surgery
• The proportion of patients with radiological fracture union at 52 and 104 weeks
• Proportion of patients with fracture healing at 16 weeks after implantation of the graft as assessed by the investigators considering clinical and radiological criteria.
• Time to fracture healing as assessed by the investigators
• The number of secondary interventions due to non-healing within 52 weeks and within 104 weeks from time of surgery comprises:
o All surgical procedures to promote fracture-healing. o All surgical procedures to perform a knee arthroplasty
o Non-invasive treatments (e.g. ultrasound) to promote fracture-healing.

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

Yes

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

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

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

Yes

E.8.1.7.1

Other trial design description

Dose-blinded

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

Autograft

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

Yes

E.8.5.1

Number of sites anticipated in the EEA

E.8.6 Trial involving sites outside the EEA

E.8.6.1

Trial being conducted both within and outside the EEA

Yes

E.8.6.2

Trial being conducted completely outside of the EEA

E.8.6.3

If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned

Australia

Canada

France

Germany

Hungary

Italy

Poland

Spain

Switzerland

United Kingdom

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

LPLV

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

E.8.9.2

In all countries concerned by the trial years

E.8.9.2

In all countries concerned by the trial months

E.8.9.2

In all countries concerned by the trial days

F. Population of Trial Subjects

F.1 Age Range

F.1.1

Trial has subjects under 18

F.1.1