Clinical Trials Register

Summary
EudraCT Number:	2011-000931-10
Sponsor's Protocol Code Number:	RGH-478-004
National Competent Authority:	Hungary - National Institute of Pharmacy
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2011-05-12
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

Hungary - National Institute of Pharmacy

A.2

EudraCT number

2011-000931-10

A.3

Full title of the trial

An Exploratory, Double-Blind, Randomized, Placebo and Active-Controlled Study to Assess the Safety and Efficacy of RGH-478 for the Treatment of Moderate to Severe Pain in Osteoarthritis of the Knee

A.3.1

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

Feltáró jellegű, kettős vak, véletlen elrendezésű, placebóval és aktív vizsgálati készítménnyel kontrollált klinikai vizsgálat az RGH-478 biztonságosságának és hatásosságának értékelésére közepes és súlyos fájdalommal járó térd osteoarthrosisban

A.4.1

Sponsor's protocol code number

RGH-478-004

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	Gedeon Richter Plc.
B.1.3.4	Country	Hungary
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	Gedeon Richter Plc.
B.4.2	Country	Hungary
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Gedeon Richter Plc.
B.5.2	Functional name of contact point	Gedeon Richter Plc.
B.5.3	Address:
B.5.3.1	Street Address	Gyömrői út 19-21.
B.5.3.2	Town/ city	Budapest
B.5.3.3	Post code	1103
B.5.3.4	Country	Hungary
B.5.6	E-mail	RA.ctaRichter@richter.hu

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	RGH-478 Capsule
D.3.2	Product code	RGH-478
D.3.4	Pharmaceutical form	Capsule
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.3.9.2	Current sponsor code	RGH-478
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 100 mg kapszula
D.2.1.1.2	Name of the Marketing Authorisation holder	Pfizer Kft.
D.2.1.2	Country which granted the Marketing Authorisation	Hungary
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	Celebrex 100 mg kapszula
D.3.2	Product code	celecoxib
D.3.4	Pharmaceutical form	Capsule
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.3.9.2	Current sponsor code	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	100
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
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

Osteoarthritis of the knee

E.1.1.1

Medical condition in easily understood language

Knee arhtrosis

térdízületi kopás

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	13.1
E.1.2	Level	LLT
E.1.2	Classification code	10023476
E.1.2	Term	Knee osteoarthritis
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

The primary objective is to preliminarily evaluate the efficacy of RGH-478 compared with placebo in patients with osteoarthritis.

E.2.2

Secondary objectives of the trial

The secondary objectives of this study are to assess the safety and tolerability of RGH-478 in patients with osteoarthritis.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

Male or female ≥ 40 years of age on the day of signing informed consent;

Diagnosis of OA of the knee for ≥ 6 months before signing informed consent according to American College of Rheumatology (ACR) criteria with X-ray confirmation of Kellgren-Lawrence grade 2 or 3 in the femoro-tibial compartment at screening and functional capacity class of I-III;

Pain of the index knee joint on more than 50% of days over the last month prior to screening requiring analgesic and/or anti-inflammatory treatment;

Currently receiving regular analgesics treatment (defined as drug intake for ≥ 4 days per week) for pain at the index knee joint. Analgesic treatment may include non-steroidal anti-inflammatory drugs ([NSAIDs] including cyclooxygenase-2 [COX-2] inhibitors), paracetamol, and/or weak opioids (e.g. tramadol) given at recommended dose ranges;

A Western Ontario & McMaster Universities Index of Osteoarthritis (WOMAC) VA3.1 pain visual analogue scale (VAS) score at Screening (Visit 1) ≥ 30 mm and ≤ 80 mm;

Willingness to abstain from use of NSAIDs (oral and topical other than the one given as study drug), other topical pain therapies (e.g., capsaicin), corticosteroids (systemic and intra-articular), viscosupplementation, and other pharmacological pain treatments during the study;

Willingness to abstain from the use of the permitted rescue medication (paracetamol) for 24 hours prior to all study visits8)

Female patients of childbearing potential must have a negative serum pregnancy test (serum beta-human chorionic gonadotropin) at screening unless they are surgically sterile or have been post-menopausal for ≥ 1 year (12 consecutive months without menses);

Women of childbearing potential must use a medically acceptable means of birth control and agree to continue its use during the study and for at least 4 weeks after the last dose of study drug. Medically acceptable forms of birth control include oral contraceptives, injectable or implantable methods, intrauterine devices, tubal ligation (if performed > 1 year before screening), or double barrier contraception. Sexually active male patients should be surgically sterile or agree to use a medically acceptable means of birth control;

Able to understand and willing to sign the informed consent prior to screening evaluations and agree to the schedule of assessments.

A WOMAC VA3.1 pain VAS score at Baseline (Visit 2) ≥ 50 mm, with an increase of ≥ 10 mm from
Screening;

A Patient’s Global Assessment (PGA) of disease activity at Baseline of fair, poor, or very poor; and

Patients need to have a minimum of 2 daily pain assessments via IVRS during the Screening Period.

E.4

Principal exclusion criteria

Surgery, including arthroscopy, of the index knee joint within 3 months of screening or any scheduled surgery or painful procedure of the index knee joint during the course of the study;

Intra-articular corticosteroid to the index knee joint within 3 months prior to screening or to any other joint within 4 weeks prior to screening;

Hyaluronic acid intra-articular injection to the index knee joint within 6 months prior to screening;

Systemic corticosteroids (oral, intramuscular, or intravenous) within 4 weeks prior to screening;

Physical therapy and other non-pharmacological pain therapy unless dose was stable for ≥ 1 months prior to screening or planning the initiation of such therapy during the study;

Nutritional supplementation for OA (unless dose was stable for ≥ 1 months prior to screening or planning the initiation of such therapy during the study;

Radiotherapy for chronic articular pain within 3 months prior to screening or planning the initiation of such therapy during the study;

Initiation of the use of medications for treating chronic pain (including anticonvulsants, tricyclic antidepressants, unselective serotonin reuptake inhibitors, norepinephrine reuptake inhibitors etc.) within 2 weeks prior to screening or planning the initiation of any new anti-pain therapy or treatment during the study;

Initiation of the use of hypnotics or change in the dosing regimen of current hypnotics including benzodiazepines and non-benzodiazepine hypnotics within 2 weeks prior to screening;

Current use of anticoagulant drugs or antiaggregants (including low-dose acetylsalicylic acid);

BMI < 18 or > 39 and/or body weight <40 kg at screening;

Clinically relevant history of hypersensitivity or allergy to study drug, celecoxib, or paracetamol or any of their excipients as well as existence of a medical condition or use of concomitant medication for which the use of celecoxib or paracetamol is contraindicated;

Known hypersensitivity to sulphonamides;

Had previously failed treatment with or showed intolerance to NSAIDs, including COX-2 inhibitors;

History of asthma, acute rhinitis, angioedema, urticaria or other allergic-type reactions after taking acetylsalicylic acid, ibuprofen, or other NSAIDs, including COX-2 inhibitors;

Any medical conditions other than pain due to OA that could interfere with study evaluations, e.g., anatomical deformities, fibromyalgia, chronic pain syndrome or other arthritic conditions other than OA of the knee;

Known or clinically suspected infection with human immunodeficiency virus, hepatitis C or B viruses;

Congestive heart failure; history of clinically significant cardiovascular disease including, but not limited to, myocardial infarction, unstable angina, peripheral arterial disease, and stroke or transient ischemic attack; uncontrolled hypertension ;

Active or history of recurrent peptic ulcer/hemorrhage or gastrointestinal perforation; history of gastrointestinal bleeding, history of inflammatory bowel disease;

History of congenital QTc prolongation or QTc duration at the screening electrocardiogram (ECG) ≥ 450 msec for men or ≥ 470 msec for women;

Severe renal or hepatic insufficiency;

Any clinically significant condition or laboratory result that in the Investigator’s judgment may affect efficacy or safety assessments or may compromise the patient’s safety during study participation, ;

History of malignancy within the past 5 years (except for basal cell carcinoma of the skin or carcinoma
in situ of the cervix that has been treated with no evidence of recurrence);

Participation in any investigational drug/device clinical study or in biological agent clinical studies
within 3 months prior to screening;

History within the previous 2 years or current evidence of drug or alcohol abuse;

Pregnant or lactating women; and

Any condition or circumstances which in the opinion of the Investigator may make a patient unlikely
or unable to complete the study or comply with study procedures and requirements, or may pose a risk
to the patient’s safety.

E.5 End points

E.5.1

Primary end point(s)

The primary efficacy endpoint will be the change from baseline to V5 (Week 4) in the WOMAC VA3.1 pain VAS subscale.

E.5.1.1

Timepoint(s) of evaluation of this end point

The primary end point will be evaluated after the study has been completed, no iterim analysis will be performed.

E.5.2

Secondary end point(s)

Change from baseline at V3 (Week 1), V4 (Week 2), and V5 (Week 4) in the average daily pain intensity score evaluated on a Numeric Rating Scale (NRS);
WOMAC VA3.1 Pain VAS subscale change from baseline at V3 (Week 1) and V4 (Week 2);
WOMAC VA3.1 Stiffness subscale change from baseline at V3 (Week 1), V4 (Week 2), and V5 (Week 4);
WOMAC VA3.1 Physical function subscale change from baseline at V3 (Week 1), V4 (Week 2), and V5 (Week 4);
WOMAC VA3.1 Global Score change from baseline at V3 (Week 1), V4 (Week 2), and V5 (Week 4);
Changes from baseline in PGA of disease activity scores at V3 (Week 1), V4 (Week 2), and V5 (Week 4);
Percent of responders according to OMERACT-OARSI criteria at V3 (Week 1), V4 (Week 2), and V5 (Week 4);
Use of rescue medication;
Exploratory evaluation of selected biomarkers of inflammation and joint/cartilage damage;
Adverse events;
Vital signs (supine heart rate and blood pressure [systolic and diastolic]);
Physical examination;
12-lead ECG; and
Clinical laboratory tests (hematology, blood chemistry, and urinalysis).

E.5.2.1

Timepoint(s) of evaluation of this end point

The secondary end points will be evaluated after the study has been completed, no iterim analysis will be performed.

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

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)

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)

Yes

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

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

Number of subjects for this age range:

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:

150

F.1.3

Elderly (>=65 years)

Yes

F.1.3.1

Number of subjects for this age range:

100

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

250

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)

Patients will receive their original, pre-study analgesic treatment once the Treatment Period is over. Follow Up Visit is planned 7-10 days after taking the last study drug and adverse events will be collected up to 30 days after Treatment Period.

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

2011-08-02

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2011-07-27

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2012-08-08

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