Clinical Trials Register

Summary
EudraCT Number:	2011-005254-53
Sponsor's Protocol Code Number:	BKOS-03
National Competent Authority:	Germany - BfArM
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2012-02-14
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

Germany - BfArM

A.2

EudraCT number

2011-005254-53

A.3

Full title of the trial

A double-blind, randomised, placebo controlled, sequential ascending dose study, to evaluate the safety, tolerability, pharmacokinetics and pharmacodynamics of single intra-articular doses of fasitibant in patients with symptomatic osteoarthritis of the knee.

A.3.1

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

A placebo-controlled study assessing the tolerability and plasma concentrations of ascending doses of fasitibant in patients with osteoarthritis of the knee.

A.3.2

Name or abbreviated title of the trial where available

ALBATROSS-2

A.4.1

Sponsor's protocol code number

BKOS-03

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	Menarini Ricerche S.p.A
B.1.3.4	Country	Italy
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	Menarini Ricerche S.p.A
B.4.2	Country	Italy
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Menarini Ricerche S.p.A
B.5.2	Functional name of contact point	Clinical Research Director
B.5.3	Address:
B.5.3.1	Street Address	Via Sette Santi 1
B.5.3.2	Town/ city	FLORENCE
B.5.3.3	Post code	50131
B.5.3.4	Country	Italy
B.5.4	Telephone number	003905556809933
B.5.5	Fax number	00390555680597
B.5.6	E-mail	acapriati@menarini-ricerche.it

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	Fasitibant chloride bis-hydrochloride
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	Intraarticular use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	Fasitibant chloride (as bis-hydrochloride)
D.3.9.1	CAS number	883969-00-4
D.3.9.2	Current sponsor code	MEN 16132
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
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	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	Fasitibant chloride bis-hydrochloride
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	Intraarticular use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	Fasitibant chloride (as bis-hydrochloride)
D.3.9.1	CAS number	883969-00-4
D.3.9.2	Current sponsor code	MEN 16132
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	2.5
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: 3
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	Fasitibant chloride bis-hydrochloride
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	Intraarticular use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	Fasitibant chloride (as bis-hydrochloride)
D.3.9.1	CAS number	883969-00-4
D.3.9.2	Current sponsor code	MEN 16132
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	5
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: 4
D.1.2 and D.1.3	IMP Role	Comparator
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	HYALART
D.2.1.1.2	Name of the Marketing Authorisation holder	MEDA Pharma GmbH&Co.KG
D.2.1.2	Country which granted the Marketing Authorisation	Germany
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	Sodium hyaluronate
D.3.4	Pharmaceutical form	Solution for injection in pre-filled syringe
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	Sodium Hyaluronate
D.3.9.1	CAS number	9067-32-7
D.3.9.4	EV Substance Code	SUB14126MIG
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	10
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.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
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

Ostoarthritis of the knee

E.1.1.1

Medical condition in easily understood language

Degeneration of the cartilage of the knee 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	14.1
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 the safety and tolerability of fasitibant up to 5 mg formulated as 1 mL solution to be given as single intra-articular (IA) administration to patients with knee osteoarthritis.

E.2.2

Secondary objectives of the trial

1) To assess main plasma pharmacokinetic parameters, including dose-proportionality of fasitibant monocomponent (up to 5 mg), of its main metabolite MEN 19148, and of fasitibant 5 mg in extemporaneous combination with sodium hyaluronate in patients with knee osteoarthritis (OA).
2) To evaluate changes in plasma or serum levels, as appropriate,of OA biomarkers and preliminary efficacy data in knee OA patients following IA single up to 5 mg doses of fasitibant alone and in combination with Sodium Hyaluronate.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1.Written informed consent.
2.Male or female patients ≥ 30 years old and a BMI < 30 kg/m².
3.Women of childbearing potential are eligible to participate in the study if their pregnancy test is negative at screening, they are not nursing, and they use an effective method of contraception.
4. Symptomatic primary or secondary knee osteoarthritis for which IA treatment is indicated.
5. Pain score >5 points assigned to the index knee at WOMAC NR 3.1-A1.
6. Pain score >12 points assigned to the index knee at WOMAC NR 3.1 A subscore. 7. Pain in the index knee on at least 50% of the days in the month preceding the screening.
8. Minimum flexion of 90 degrees in both knees.
9. Ability to perform the 15 m walk test without the support of crutches or other assistive devices.
10. Willingness to discontinue all pain or OA medication.
11. Willingness to refrain from paracetamol use 48 hours prior to each study visit.

E.4

Principal exclusion criteria

1. Inability to personally provide written informed consent.
2. Inability to understand or collaborate throughout the study.
3. Patients who participated in another clinical trial within 30 days prior randomisation.
4. Patients with severe OA of the knee.
5. Knee condition representing an indication for surgery .
6. Inflammatory or crystal arthropathies.
7. Patients with acute fractures, severe loss of bone density, bone necrosis.
8. Patients with isolated patella-femoral syndrome or chondromalacia.
9. Patients with OA predominant in the lateral compartment.
10. Patients with any other clinically significant and unstable disease or condition interfering with the evaluation of the safety of study treatment.
11. Major injury or surgery to the index knee within the previous 12 months prior to screening.
12. Severe hip OA ipsilateral to index knee.
13. Any pain >3 points in the numerical rating (NR) scale (0-10) that could interfere with the assessment of the index knee pain.
14. Any pharmacological or non-pharmacological treatment started or changed during 4 weeks prior to randomisation.
15. Use of systemic or topical corticosteroids >10 mg prednisolone equivalent.
16. Use of any pain or OA medication.
17. Any acute or newly diagnosed disease/condition requiring treatment.
18. Any unstable chronic disease/condition requiring treatment modification.
19. History of hypersensitivity to drugs including paracetamol.
20. Patient with known hypersensitivity to hyaluronate preparations.
21. Patients with any of the following
a) clinically relevant cardiovascular, pulmonary, gastrointestinal, haematological, neurologic-psychiatric or infectious diseases.
b) clinically relevant abnormal safety laboratory test result and/or clinically relevant abnormalities in vital signs and/or ECG parameters at screening (Visit 1) and/or prior to dose administration (Visit 2).
22. Patients with liver disease
23. Patients with moderate or severe renal insufficiency (Creatinie Clearence [CrCl according to Cockgroft-Gault formula] < 60 mL/min).
24. Any sign of significant inflammation or infection.
25. Any skin disorder or infection overlying the index knee.
26. Previous infection of the index knee.
27. Any IA or local peri-articular punction, injection, or surgery to the index knee during the 3 months prior to screening.
28. Patients with bleeding diathesis or on therapy with anticoagulants.
29. Significant peri-articular calcification.
30. Previous ligament reconstruction at the index knee.

E.5 End points

E.5.1

Primary end point(s)

Safety and tolerability of study treatments:
-Changes in vital signs (blood pressure, pulse rate, respiratory rate, body temperature; 12-lead electrocardiogram (ECG) parameters; laboratory safety battery tests, and physical examination at End of Study versus baseline.
-Incidence and severity of adverse events occurring between randomisation and End of Study.

E.5.1.1

Timepoint(s) of evaluation of this end point

Between randomisation (T0) and two weeks after administration of study treatments (T14 +/- 2 Days).

E.5.2

Secondary end point(s)

Pharmacokinetics of the study treatments in terms of absorption, distribution, metabolism and elimination of the study treatments, including analysis of dose proportionality.
This includes also the pharmacokinetic analysis of the main metabolite of fasitibant (MEN 19148), the mono-hydroxylated derivative formed by oxidative metabolism by the cytochrome P450 enzyme.

Pharmacodynamics of the study treatments:
Analysis of Biomarkers of osteoarthritis, inflammation and cartilage degeneration.

Clinical Efficacy of study treatments:
Assessment of OA symtoms (pain, walking pain, stiffness) using validated standard questionnaires (WOMAC 3.1 NR).
Assessment of pain at rest and after 15 metres walk
Patients' and Physicians' global assessment of efficacy.

E.5.2.1

Timepoint(s) of evaluation of this end point

Pharmacokinetics:
Between time of dosing (T0) and defined time points until 1 week (T7 +/-2 days) after treatment adminsitration.

Pharmacodynamics:
OA Biomarkers: Between time of dosing (T0) and 1 week (T7 +/-2 days) after treatment adminsitration.

Clinical Efficacy:
Between time of dosing (T0), 1 week (T7 +/-2 days) and 2 weeks (T14 +/-2 days) after treatment adminsitration.

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

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)

Yes

E.7.1.1

First administration to humans

E.7.1.2

Bioequivalence study

E.7.1.3

Other

Yes

E.7.1.3.1

Other trial type description

Pharmacokinetics of fasitibant (up to 5 mg) and its main metabolite MEN 19148 in humans

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

Yes

E.8.1.7.1

Other trial design description

Sequential cohorts:fasitibant 1, 2.5, 5mg vs placebo; fasitiband5mg+hyaluronate (HA) vs placebo+HA

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

Yes

E.8.2.3.1

Comparator description

Comparison Fasitibant 5mg+Hyaluronate 20mg vs Placebo+Hyaluronate 20mg (to assess additive effects)

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

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

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.1.1.1

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

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)

Standard medical care of knee osteoarthritis according to the investigators' judgement to be applied after patients have terminated the study.

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

2012-05-04

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2012-05-14

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2013-02-01

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