Clinical Trials Register

Summary
EudraCT Number:	2011-003059-20
Sponsor's Protocol Code Number:	EMR700692_006
National Competent Authority:	Denmark - DHMA
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2013-06-06
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

Denmark - DHMA

A.2

EudraCT number

2011-003059-20

A.3

Full title of the trial

A multicenter, randomized, double-blind, placebo-controlled, parallel-group trial to investigate the efficacy and safety of different intra-articular (i.a.) dosages of sprifermin in subjects with primary osteoarthritis of the knee (FORWARD)

A.3.1

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

A study to investigate the safety and effectiveness of different doses of a new drug (sprifermin- also called AS902330) in patients with osteoarthritis of the knee

A.3.2

Name or abbreviated title of the trial where available

FORWARD

A.4.1

Sponsor's protocol code number

EMR700692_006

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@merckgroup.com

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	Sprifermin 100 mcg
D.3.2	Product code	AS902330 100 mcg
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.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	Sprifermin 30 mcg
D.3.2	Product code	AS902330 30 mcg
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.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

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

Primary osteoarthritis

E.1.1.1

Medical condition in easily understood language

A disease characterized by deterioration of cartilage and its underlying bone within a joint.

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	18.1
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

To evaluate structural changes in cartilage thickness in the total femorotibial joint of the target knee in terms of imaging by magnetic resonance imaging (MRI)

E.2.2

Secondary objectives of the trial

* To evaluate different dose regimens of sprifermin
* To evaluate changes in symptoms of osteoarthritis (OA)
* To evaluate changes in structure in terms of imaging by X-ray
* To evaluate other changes in cartilage morphology in terms of imaging by MRI (sub-regions)
* To evaluate changes in physical functioning
* To evaluate the safety of sprifermin
* To evaluate the pharmacokinetics (PK) of sprifermin in serum and in synovial fluid following i.a. injection

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

The trial will enroll adult subjects of either sex with primary femorotibial osteoarthritis according to American College of Rheumatology (ACR) clinical and radiographic criteria who have Kellgren-Lawrence grades of 2 or 3 and a minimum joint space width (JSW) of ≥ 2.5 mm in the medial compartment.

Subjects must have pain in the target knee on most days and/or require symptomatic treatment of knee pain with paracetamol (acetaminophen), systemic non-steroidal anti-inflammatory drugs (NSAIDs) including COX-2 selective inhibitor (coxibs), or tramadol on most days of the previous month, and must have both:
* A history of pain due to OA in the target knee for at least 6 months, and
* Pain score for the target knee of 4 to 9 points in response to Question 1 of the WOMAC pain index(“how much pain have you had [in the target knee, over the past 48 hours] when walking on a flat
surface?”) at screening and baseline, after washout of at least 5-half-lives of analgesic medication(s): acetaminophen, topical or oral systemic NSAIDS, coxibs, opioids, and/or tramadol.

Women of childbearing potential must use a form of contraception with a failure rate of less than 1% per year throughout the trial.

E.4

Principal exclusion criteria

Main exclusion criteria are malalignment of > 5 degrees in the femorotibial axis of the target knee, clinical signs of inflammation (i.e., redness) in the target knee, i.a. administration of corticosteroids or hyaluronic acid into either knee within 6 months before screening, any plan for knee surgery (affecting either the target or the contralateral knee) within the next two years, concomitant conditions or treatments deemed to be incompatible with trial participation, contraindications to MRI scanning (including inability to fit in the scanner or knee coil), pregnancy or breastfeeding, participation in another clinical trial within the past 30 days, and legal incapacity or limited legal capacity.

E.5 End points

E.5.1

Primary end point(s)

Change from baseline in cartilage thickness in the total femorotibial joint as evaluated by MRI at 2 years

E.5.1.1

Timepoint(s) of evaluation of this end point

at 2 years

E.5.2

Secondary end point(s)

Secondary efficacy endpoints are:
* Changes from baseline in the WOMAC total score and in the WOMAC pain, function, and stiffness index scores over 2 years
* Change from baseline in the 20-meter walk test over 2 years
* Change from baseline in the PGA over 2 years
* Change from baseline in minimal joint space width in the medial and lateral compartments as evaluated by X-ray over 2 years
* Change from baseline in cartilage thickness in the medial and lateral compartments as well as in the total femorotibial joint over 2 years
* Change from baseline in cartilage volume in the medial and lateral compartments as well as in the total femorotibial joint over 2 years
* Synovial fluid levels of sprifermin/FGF-18
* Serum levels of sprifermin/FGF-18

Safety endpoints are:
* Nature, incidence and severity of local and systemic AEs
* Incidence of acute inflammatory reactions (AIRs), defined as increase of pain by 30 mm on a 100 mm
visual analogue scale (VAS) and a self-reported synovial fluid effusion (i.e., joint swelling) within 3 days following i.a. injection
* Changes in laboratory safety parameters, vital signs, 12-lead electrocardiogram (ECG) parameters, weight, and physical examinations
* Incidence of surgical interventions in the target knee (including any surgical revision, cartilage removal, or any other type of surgical intervention).
* Occurrence of binding and neutralizing antibodies to sprifermin/FGF-18

E.5.2.1

Timepoint(s) of evaluation of this end point

DBPC phase:
* Changes from baseline in the WOMAC total score and in the WOMAC pain, function, and stiffness: over 2 years
* Change from baseline in the 20-meter walk test: over 2 years
* Change from baseline in the PGA: over 2 years
* Change from baseline in minimal joint space width in the medial and lateral compartments as by X-ray: over 2 years
* Change from baseline in cartilage thickness in the medial and lateral compartments: over 2 years
* Change from baseline in cartilage volume in the medial and lateral compartments as well as in the total femorotibial joint: over 2 years
* Synovial fluid levels of sprifermin/FGF-18: at W0, W1, W2, W26, W27 and W28
* PK Serum collection: W0, W2 and W28
* AEs: Continuous

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

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

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

Argentina

Czech Republic

Denmark

Estonia

Hong Kong

Poland

Romania

United States

E.8.7

Trial has a data monitoring committee

Yes

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 phase. 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:

270

F.1.3

Elderly (>=65 years)

Yes

F.1.3.1

Number of subjects for this age range:

275

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

193

F.4.2

For a multinational trial

F.4.2.1

In the EEA

452

F.4.2.2

In the whole clinical trial

545

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 judgement, 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

2013-06-06

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2013-06-07

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2019-05-07

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