Clinical Trials Register

Summary
EudraCT Number:	2012-001431-31
Sponsor's Protocol Code Number:	EMR700692-007
National Competent Authority:	Belgium - FPS Health-DGM
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2013-03-27
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

Belgium - FPS Health-DGM

A.2

EudraCT number

2012-001431-31

A.3

Full title of the trial

A multicenter, randomized, double-blind, placebo-controlled, parallel-group, Phase II trial to investigate the efficacy and safety of 30 mcg and 100 mcg AS902330 given as one cycle of three intra-articular knee injections once a week for three weeks as an adjunct treatment to patients following microfracture surgery for cartilage injury of the knee.

A.3.1

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

Phase II Trial of AS902330 as Adjunct to Microfracture in Cartilage Injury

A.3.2

Name or abbreviated title of the trial where available

Phase II Trial of AS902330 as Adjunct to Microfracture in Cartilage Injury

A.4.1

Sponsor's protocol code number

EMR700692-007

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	Merck KGaA
B.1.3.4	Country	Germany
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	Merck KGaA
B.4.2	Country	Germany
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Merck KGaA
B.5.2	Functional name of contact point	Communication Centre Merck KGaA
B.5.3	Address:
B.5.3.1	Street Address	Frankfurter Straße 250
B.5.3.2	Town/ city	Darmstadt
B.5.3.3	Post code	64293
B.5.3.4	Country	Germany
B.5.4	Telephone number	+496151725200
B.5.5	Fax number	+496151722000
B.5.6	E-mail	service@merck.de

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	AS902330 30mcg
D.3.2	Product code	AS902330
D.3.4	Pharmaceutical form	Powder and solvent for solution for injection
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Intraarticular use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	Sprifermin
D.3.9.2	Current sponsor code	AS902330
D.3.10	Strength
D.3.10.1	Concentration unit	µg microgram(s)
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	30
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.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	AS902330 100mcg
D.3.2	Product code	AS902330
D.3.4	Pharmaceutical form	Powder and solvent for solution for injection
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Intraarticular use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	Sprifermin
D.3.9.2	Current sponsor code	AS902330
D.3.10	Strength
D.3.10.1	Concentration unit	µg microgram(s)
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	100
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
D.8 Placebo: 1
D.8.1	Is a Placebo used in this Trial?	Yes
D.8.3	Pharmaceutical form of the placebo	Powder and solvent for solution for injection
D.8.4	Route of administration of the placebo	Intraarticular use
D.8 Placebo: 2
D.8.1	Is a Placebo used in this Trial?	Yes
D.8.3	Pharmaceutical form of the placebo	Powder for concentrate for solution for injection/infusion
D.8.4	Route of administration of the placebo	Intraarticular use

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

Knee Cartilage Injury

E.1.1.1

Medical condition in easily understood language

Injury of the knee Cartilage. Mains symptoms of cartilage lesions are
pain, joint swelling, and loss of function.

E.1.1.2

Therapeutic area

Diseases [C] - Injuries, poisonings, and occupational diseases [C21]

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	15.1
E.1.2	Level	PT
E.1.2	Classification code	10007710
E.1.2	Term	Cartilage injury
E.1.2	System Organ Class	10022117 - Injury, poisoning and procedural complications

E.1.3

Condition being studied is a rare disease

E.2 Objective of the trial

E.2.1

Main objective of the trial

The primary objective is to evaluate the effect of AS902330 intra-articular (i.a.) knee injections as adjunct to microfracture (MFx) surgery on the composition of the refilled cartilage in the target knee, as measured by delayed gadolinium-enhanced magnetic resonance imaging of cartilage (dGEMRIC) T1 relaxation time at 6 months after MFx surgery.

E.2.2

Secondary objectives of the trial

To further support the efficacy and safety of AS902330 as an adjunct to MFx for cartilage injury repair through symptomatic outcomes and quantitative magnetic resonance imaging (MRI) measurement.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

• adults subjects; 18 to 60 years old of either sex with symptomatic knee cartilage injury who are eligible for MFx surgery on the femoral articular surfaces, with intact subchondral bone.
• Intraoperative inclusion criteria require that there be one or two focal chondral lesions per target knee and that each lesion satisfy all of the following criteria after peripheral debridement to healthy cartilage: (1) area between 1 and 4 cm2 (inclusive), (2) depth ≤ 6 mm, and (3) arthroscopic confirmation that the lesion is a non-osteochondritis dissecans (OCD) lesion between International Cartilage Repair Society (ICRS) grades I and III (D); a grade III non-OCD lesion is equivalent to an Outerbridge grade IV lesion with minimal subchondral bone loss.
• Subjects must have moderate to severe pain in the target knee prior to surgery, with an average score ≥ 4.0 on the NRS of pain intensity over 7 consecutive days within 30 (+15) days before surgery.
• Subjects must be willing to comply with postoperative and routine clinical and radiographic evaluations, and to follow a standardized rehabilitation program.
• Women of childbearing potential must use a form of contraception with a failure rate of less than 1% per year for the first 24 months of the trial. The use of contraception is also recommended throughout the remaining duration of the trial, due to the planned MRI scans involving gadolinium contrast medium (which is contraindicated in case of pregnancy or breastfeeding) and also because of potential confounding effects of pregnancy on symptoms and trial assessments.
• Written informed consent must be obtained prior to any trial-related activity.

E.4

Principal exclusion criteria

Main exclusion criteria include specified previous knee surgeries and procedures, more than two chondral lesions or presence of bipolar (or “kissing”) lesions in the target knee, need for concurrent partial meniscectomy, need for any other major concomitant procedure affecting the target knee or for bilateral knee surgery, osteoarthritis in the target knee, body mass index (BMI) > 35 kg/m², malalignment of the target knee of > 5 degrees measured from the mechanical axis, concomitant conditions or treatments that the investigator considers to constitute a risk or contraindication for participation in the trial or that could interfere with the trial objectives, conduct or evaluation, contraindications to MRI scanning, pregnancy or breastfeeding, regular smoking of more than 10 cigarettes or equivalent per day within the past 6 months, participation in another clinical trial within the past 30 days (or 5 half-lives of the investigated compound,whichever is longer), and legal incapacity or limited legal capacity.

E.5 End points

E.5.1

Primary end point(s)

Composition of the refilled cartilage, at 6 months post-MFx surgery as measured by the dGEMRIC T1 relaxation time.

E.5.1.1

Timepoint(s) of evaluation of this end point

The primary endpoint will be assessed at 6 months

E.5.2

Secondary end point(s)

Efficacy (in order of priority):
•Composition of the refilled cartilage, as measured by dGEMRIC T1 relaxation time, at each MRI assessment time point beyond Month 6 post-MFx surgery.
•Reduction in subject-reported knee pain intensity and improvement in subject-reported knee function as measured by change from baseline in the KOOS sub-scores for Pain and activities of daily living (ADL) at each KOOS time point.
•Change from baseline in (a) the (subject-reported) Total KOOS score, (b) each of the three other dimensions of the KOOS sub-scores (Other Symptoms, Knee-related Quality of Life, and Function in Sports and Recreational Activities [FSR]), and (c) the Total KOOS minus the FSR sub-score, at each KOOS time point.
•Change from baseline in subject-reported knee pain using an NRS pain diary at each NRS time point
•Changes from baseline in the subject-reported LEAS at each LEAS time point.
•Changes from baseline in the physician-reported Lysholm Knee Scale score at each Lysholm time point.
•Composition of the refilled cartilage as evaluated through T2 mapping at each MRI time point.
•Composition of the refilled cartilage as evaluated through T1 rho (non-contrast) imaging at each MRI time point.
•Volume of refilled cartilage at each MRI time point.
•Cartilage fill as assessed by MOCART scores at each MOCART time point.
•6-minute walk test at each specified walk-test time point (as an objective measure of function).

E.5.2.1

Timepoint(s) of evaluation of this end point

1) At 12, 18, 24, 36, 48 & 60 months
- Composition of the refilled cartilage, by dGEMRIC T1 relaxation time
- Change from baseline in the KOOS sub-scores for Pain and ADL
- Composition of the refilled cartilage through T2 mapping
- Composition of the refilled cartilage through T1 rho (non-contrast) imaging
- Volume of the refilled cartilage
- Cartilage fill by MOCART

2) At 9, 12, 18, 24, 30, 36, 42, 48, 54 & 60 months
- Change from baseline in Total KOOS score; each of the 3 other dimensions of the KOOS sub-scores, and Total KOOS minus the FSR sub-score
- Change from baseline in subject-reported knee pain using an NRS pain diary
- Change from baseline in the subject-reported LEAS
- Change from baseline in the physician-reported Lysholm Knee Scale score
- 6-minute walk test

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

Yes

E.6.7

Pharmacodynamic

Yes

E.6.8

Bioequivalence

E.6.9

Dose response

Yes

E.6.10

Pharmacogenetic

Yes

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

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

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

Belgium

United States

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

For administrative and safety reporting purposes, the end of the trial will be defined as the date of the final clinical database lock at the end of the Extended Follow-up Period. This provides for a single and conservative definition across all trial sites.

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

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)

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.4.2

For a multinational trial

F.4.2.1

In the EEA

F.4.2.2

In the whole clinical trial

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 who have completed the trial or have withdrawn early should be managed in accordance with the investigator’s clinical judgment, as appropriate for each subject’s individual medical needs.

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

2013-05-02

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2013-04-08

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2013-09-10

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