Clinical Trials Register

Summary
EudraCT Number:	2015-002933-23
Sponsor's Protocol Code Number:	DAR-INT-14-01
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:	2017-06-30
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

2015-002933-23

A.3

Full title of the trial

AN INTERNATIONAL, MULTICENTRE, DOUBLE-BLIND, RANDOMISED STUDY OF THE EFFECT OF DIACEREIN VS CELECOXIB ON SYMPTOMS AND STRUCTURAL CHANGES IN SYMPTOMATIC KNEE OSTEOARTHRITIS PATIENTS AS ASSESSED BY MAGNETIC RESONANCE IMAGING

A.3.1

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

A.4.1

Sponsor's protocol code number

DAR-INT-14-01

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	TRB CHEMEDICA INTERNATIONAL SA
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	TRB CHEMEDICA INTERNATIONAL SA
B.4.2	Country	Switzerland
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	CHU Brugmann
B.5.2	Functional name of contact point	National coordinating investigator
B.5.3	Address:
B.5.3.1	Street Address	Place A.Van Gehuchten 4
B.5.3.2	Town/ city	Bruxelles
B.5.3.3	Post code	1020
B.5.3.4	Country	Belgium
B.5.4	Telephone number	322477 3312
B.5.6	E-mail	pieter.reynders@chu-brugmann.be

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	Diacerein
D.2.1.1.2	Name of the Marketing Authorisation holder	TRB Chemedica (Austria) GmbH
D.2.1.2	Country which granted the Marketing Authorisation	Austria
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	Capsule, hard
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Oral use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	DIACEREIN
D.3.9.1	CAS number	13739-02-1
D.3.9.4	EV Substance Code	SUB07060MIG
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	50
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	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	Celebrex
D.2.1.1.2	Name of the Marketing Authorisation holder	Pfizer Canada
D.2.1.2	Country which granted the Marketing Authorisation	Canada
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	Capsule, hard
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Oral use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	Celecoxib
D.3.9.1	CAS number	169590-42-5
D.3.9.3	Other descriptive name	CELECOXIB
D.3.9.4	EV Substance Code	SUB01143MIG
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	200
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	Capsule, hard
D.8.4	Route of administration of the placebo	Oral use

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

Pain reduction in symptomatic knee osteoarthritis (OA)

E.1.1.1

Medical condition in easily understood language

Pain reduction in symptomatic knee osteoarthritis (OA)

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	20.0
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

The primary objective of this study is to show that Diacerein is non-inferior to Celecoxib in terms of pain reduction (WOMAC A pain subscale) after 182 days of treatment in symptomatic knee OA patients.

E.2.2

Secondary objectives of the trial

Exploratory objectives include analyses comparing Diacerein with Celecoxib on other functional parameters and structural changes as assessed by MRI after 24 months (728 days) and safety of both products after short (182 days) and long-term (728 days) treatment.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1. Men and women of at least 50 years of age;
2. Patients followed in an ambulatory clinic;
3. Patients presenting primary OA of the knee according to ACR criteria;
4. Patients with OA of radiological stages 2 and 3 according to Kellgren-Lawrence;
5. Patients with a minimum joint space width ≥2 mm in the medial tibio-femoral compartment on standing knee X-ray (MRI structural study only);
6. Patients with knee pain on most days of the month before entering into the study;
7. Patients with a VAS pain score (0-100 mm) while walking on a flat surface ≥ 40 mm (Visit 1 (Screening)and Visit 2 (Inclusion Visits));
8. Patients with no clinically significant laboratory abnormalities in the judgment of the investigator;
9. Female patients who are postmenopausal with confirmed amenorrhea for at least one year before entering this study and those who underwent tubal ligation, oophorectomy or hysterectomy must agree to an hormonal (FSH) dosage at Screening visit ;
10. Patients agreeing to sign the Informed Consent Form prior to any study-related activities after having been clearly informed of its methods and constraints;
11. Patients not taking part in another clinical study;
12. Patients agreeing to respect the protocol by attending the visits related to the study.

E.4

Principal exclusion criteria

Criteria Related to Individual Characteristics of the Patient
1. Patients with secondary knee OA
2. Patients with known hypersensitivity to Diacerein or to anthraquinone-containing product, hypersensitivity to Celecoxib, who have demonstrated allergic-type reactions to sulphonamides, experienced asthma, urticaria or allergic-type reactions after taking sulphonamides, aspirin (acetyl salicylic acid [ASA]), lactose, NSAIDs, acetaminophen
or paracetamol;
3. Patients with a known history of diarrhoea, more particularly if 65 years of age and older.
4. Patients with active malignancy of any type or history of a malignancy within the last five years other than basal cell carcinoma;
5. Patients with other bone and articular diseases (antecedents and/or current signs) such as chondrocalcinosis, Paget’s disease of the ipsilateral limb to the target knee, rheumatoid arthritis, aseptic osteonecrosis, gout, septic arthritis, ochronosis, acromegaly, haemochromatosis, Wilson’s disease, osteochondromatosis, seronegative spondylo-arthropathy, mixed connective tissue disease, collagen vascular disease, psoriasis, inflammatory bowel disease;
6. Pain in other parts of the body greater than the knee pain that could interfere with the evaluation of the index joint;
7. Patients with fibromyalgia;
8. Patients with isolated knee lateral compartment OA defined by joint space loss in the lateral compartment only;
9. Patients with Class IV functional capacity using the American Rheumatism Association criteria;
10. Patients who have had surgery in any lower limb or arthroscopy, aspiration or lavage in any lower limb joint within 180 days of the Inclusion Visit (Visit 2);
11. Patients who have had meniscal surgery on the study knee;
12. Patients who have undergone total knee replacement in the contralateral knee within 182 days prior to the Screening Visit (Visit 1).
13. Patients with co-morbid conditions or joint deformity that restrict knee function;
14. Patients with a history ofheart attack or stroke, or who have had serious diseases of the heart such as congestive heart failure (functional classes II-IV of the NYHA);
15. Patients who have significant risk factors for heart attack or stroke will be assessed carefully. Risk factors for heart attack and stroke include high blood pressure (treated or untreated), high cholesterol, diabetes and smoking. The global risk assessment will be assessed using the American Heart Association (AHA) assessment of CV risk tables. Patients with high risk of CV events will be excluded;
[continues to 31 criteria]
32. Patients using corticosteroids (oral, injectable; exception of intraarticular/soft tissueinjection at the exclusion of the target knee), indomethacin, therapeutic dose of glucosamine, chondroitin sulfate or Diacerein or ASU during the 12 weeks preceding inclusion (intraarticular injections of corticosteroids in the contralateral knee is allowed during the study);
33. Patients using hyaluronic acid (intra-articular target knee) during the 26 weeks preceding inclusion;
34. Patients using natural health products (e.g. capsaicin, boswellia, willow bark), and creams and analgesic gels (e.g. camphor and alcohol based gels) during one week preceding inclusion;
35. Patients using natural health products susceptible to increase the risk of bleeding (e.g. garlic, dong quai, etc.) during one week preceding inclusion;
36. Patients receiving radioactive synovectomy (target knee) during the 12 weeks preceding inclusion;
37. Patients who are taking NSAIDs and do not want to stop during the study;
38. If treatment of osteoporosis (bisphosphonates, SERMS, TSH) is necessary, it will have to be continued, unmodified, for the entire duration of the study;
39. Patients who have used compounds containing non-approved agents for arthritis or agents claiming to possess disease/structure-modifying properties in the 14 days prior to the Inclusion Visit (Visit 2);
40. Patients who have used medications with MMP-inhibitory properties (e.g. tetracycline or structurally related compounds) within 28 days prior to the Inclusion Visit (Visit 2);
41. Patients who require acetaminophen or paracetamol at daily doses >2000 mg (2g) on a regular basis;
42. Patients who are taking alaxative, lithium carbonate, phenytoin or anticoagulants (with the exception of ASA up to a maximum daily dose of 325 mg);
43. Patients who have received chondrocyte transplants or underwent other type of cartilage repair procedures in the target joint;
44. Patients who use oral or topical coxibs;
45. Patients who use calcitonin;
46. Patients who use immunosuppressive drugs.
Criteria Related to Magnetic Resonance Imaging (MRI)
47. Patients presenting a counter-indication to an MRI examination;
48. Patients whose Inclusion Visit cartilage volume cannot be calculated from the MRI due to advanced OA disease;

E.5 End points

E.5.1

Primary end point(s)

Due to the design of the study, two sets of statistical analyses will be performed: one after the completion of the 6 months treatment phase of the study in the 400 enrolled patients and another analysis after the completion of 24 months treatment phase in the 100 preselected patients from investigational centres in Canada.
Primary Study Endpoint: Change from baseline (Visit 2, D0) in WOMAC Pain subscale after 182 days of treatment.

E.5.1.1

Timepoint(s) of evaluation of this end point

After 182 days of treatment from visit 2 (D0)

E.5.2

Secondary end point(s)

OA structural changes assessed by MRI
 Cartilage volume loss from baseline (Visit 2) at D728 in the global knee and in the medial and lateral compartments.
 Change from baseline (Visit 2) at D728 in BML score.
 Change from baseline (Visit 2) at D728 in synovitis (synovial membrane thickness).
Signs and symptoms of OA
 Change from baseline (Visit 2) in WOMAC Pain score at D728.
 Change from baseline (Visit 2) in WOMAC Stiffness and WOMAC function score at D182 and D728.
 Change from baseline (Visit 2) in Visual analogic scale (VAS - Huskisson’s) at D182 and D728.
 Percentage of OARSI (Osteoarthritis Research Society International) responders at D182 and D728.
 Percentage of patients with joint swelling and effusion at D182 and D728.
 Percentage of patients consuming rescue medication at D182 and D728.
 Change from baseline (Visit 2) in Patient’s global assessment of disease activity at D182 and D728.
 Change from baseline (Visit 2) in Investigator’s global assessment of disease activity at D182 and D728.
 Patient’s global assessment of response to therapy at D182 and D728.
 Investigator’s global assessment of response to therapy at D182 and D728.
 Change from baseline in (Visit 2) in Physical Component Summary (PCS) and Mental Component Summary (MCS)scores from the SF-36 at D182 and D728.
Safety Evaluation
 Incidence of adverse events
 Laboratory tests
 Vital signs

E.5.2.1

Timepoint(s) of evaluation of this end point

At D182 and/or D728 (6 months or 24 months) from Visit 2 (D0)

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

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)

E.7.3

Therapeutic confirmatory (Phase III)

Yes

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)

Yes

E.8.2.2

Placebo

E.8.2.3

Other

Yes

E.8.2.3.1

Comparator description

Celecoxib

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

Austria

Belgium

Canada

Czech Republic

Spain

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

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:

280

F.1.3

Elderly (>=65 years)

Yes

F.1.3.1

Number of subjects for this age range:

120

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

F.3.3.1

Women of childbearing potential not using contraception

F.3.3.2

Women of child-bearing potential using contraception

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

250

F.4.2.2

In the whole clinical trial

400

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)

None

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

2017-07-20

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2017-09-12

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2018-06-26

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