Clinical Trials Register

Summary
EudraCT Number:	2015-001136-37
Sponsor's Protocol Code Number:	CR4056-2-01
National Competent Authority:	UK - MHRA
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2015-05-18
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

UK - MHRA

A.2

EudraCT number

2015-001136-37

A.3

Full title of the trial

A randomized, double-blind, parallel group, placebo-controlled study to evaluate the efficacy, safety and tolerability of CR4056 administered for 2 weeks in patients with osteoarthritis of the knee with moderate to severe chronic pain (with or without a neuropathic component)

A.3.1

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

A research study to evaluate the efficacy, safety and tolerability of the medicine CR4056 administered for 2 weeks to patients with knee osteoartritis affected by moderate to severe chronic pain.

A.4.1

Sponsor's protocol code number

CR4056-2-01

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	Rottapharm Biotech S.r.l.
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	Rottapharm Biotech S.r.l.
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	Rottapharm Biotech S.r.l.
B.5.2	Functional name of contact point	Clinical Research Manager
B.5.3	Address:
B.5.3.1	Street Address	Via Valosa di Sopra 9
B.5.3.2	Town/ city	Monza
B.5.3.3	Post code	20900
B.5.3.4	Country	Italy
B.5.4	Telephone number	+390397390229
B.5.5	Fax number	+300397390615
B.5.6	E-mail	Nadia.Brambilla@rottapharmbiotech.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	CR4056
D.3.2	Product code	CR4056
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	CR4056
D.3.9.1	CAS number	1004997-71-0
D.3.9.2	Current sponsor code	CR4056
D.3.9.3	Other descriptive name	CR4056
D.3.9.4	EV Substance Code	SUB168653
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.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	CR4056
D.3.2	Product code	CR4056
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	CR4056
D.3.9.1	CAS number	1004997-71-0
D.3.9.2	Current sponsor code	CR4056
D.3.9.3	Other descriptive name	CR4056
D.3.9.4	EV Substance Code	SUB168653
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
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

Moderate to severe chronic pain due to knee osteoarthritis with or without neuropathic component.

E.1.1.1

Medical condition in easily understood language

Chronic pain in patients affected by osteoarthritis of the knee

E.1.1.2

Therapeutic area

Analytical, Diagnostic and Therapeutic Techniques and Equipment [E] - Anesthesia and Analgesia [E03]

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	18.0
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

To assess the efficacy of CR4056 on pain (with or without a neuropathic component) in patients with osteoarthritis (OA) of the knee.

E.2.2

Secondary objectives of the trial

To evaluate the safety and tolerability of CR4056 in patients with OA of the knee.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1. Signed and dated informed consent obtained before undergoing any trial-specific procedure
2. Male or female aged ≥40 years and ≤75.
3. Diagnosis of primary OA of the knee of ≥6 months before the Screening Visit. The diagnosis must be confirmed at Screening Visit based on American College of Radiology (ACR) clinical and radiological criteria (X-ray must be performed during Screening Visit if not already available in the 24 months preceding the study):
-Knee pain
-X-ray osteophytes and at least one of the following:
age >50 years
morning stiffness <30 minutes duration
crepitus on active motion
4. Kellgren-Lawrence score II-III
5. Value ≥3 and ≤9 points on the WOMAC Pain Subscale (Appendix I), regardless of current analgesic/anti-inflammatory treatment at screening
6. Pain present for ≥15 days of each month in the 3 months before study entry
7. Willing and able to comply with the scheduled study visits, the treatment plan, and all study procedures.

E.4

Principal exclusion criteria

1. Rheumatological diseases other than OA (e.g., rheumatoid arthritis, other inflammatory arthritis, acute joint trauma, gout, pseudo gout, Paget’s disease).
2. Clinical diagnosis of fibromyalgia.
3. Severe pain (regardless of the location of pain) caused by other diseases, trauma, or surgery.
4. In case of multiple painful OA joints, primary location of pain other than the knee.
5. Joint replacement at any knee.
6. Significant surgical procedures (other than joint replacement) at any knee ≤12 months before the Screening Visit.
7. Planned surgical procedure at any knee during the study.
8. Thrombocytopenia or any coagulation or hematopoietic disease.
9. Seizure (excluding pediatric febrile seizures), schizophrenia, bipolar disorder, uncontrolled major depression, generalized anxiety disorder (≤6 months before the Screening Visit). Patients who are on stable therapy for depression or anxiety (except on the medications reported in Appendix IV) are eligible for the study.
10. Cardiac arrhythmia, congestive heart failure, coronary heart disease, class III/IV angina, acute myocardial infarction (≤6 months before the Screening Visit).
11. Acute hepatitis (≤3 months before the Screening Visit), chronic hepatitis and HIV infection.
12. Malignancy (other than basal cell carcinoma of the skin) active ≤12 months before the Screening Visit.
13. Patients with a personal or a family history of gallstone disease.
14. Stroke, intracranial hematoma, moderate or severe traumatic brain injury (Glasgow coma scale <13 or loss of consciousness for more than 30 minutes) or an intracranial operation ≤12 months before the Screening Visit.
15. History of alcohol or drug abuse ≤12 months before the Screening Visit.
16. Known allergy or hypersensitivity to paracetamol.
17. Significant respiratory disease (if treatment with prohibited medication, e.g. systemic steroids, is required)
18. Gastrointestinal diseases that are known to interfere with the absorption or excretion of medications.
19. Any clinically relevant disease that in the Investigator’s opinion may affect efficacy or safety assessments or may compromise the subject’s safety during trial participation, (gastrointestinal, blood, endocrine, metabolic, neurological, or psychiatric disorders).
20. Platelet count <200.000/μL.
21. Serum alkaline-phosphatase, or gamma-glutamyl-transferase, or lipase greater than 3-fold the upper limit of normal (ULN); alanine aminotransferase, or aspartate aminotransferase, or total bilirubin greater than 2-fold ULN.
22. Estimated creatinine clearance less than 60 mL/min/1.73 m2 (MDRD).
23. 12-lead electrocardiogram (ECG) with clinically relevant findings.
24. Treatment with strong opioids (≤30 days before the Screening Visit). Patients who are taking weak and atypical opioids can be enrolled in the study.
25. Intra-articular visco-supplementation at any knee (≤6 months before the Screening Visit).
26. Intra-articular or topical steroids, topical NSAIDs at any knee (≤3 months and ≤ 1 week before the Screening Visit, respectively).
27. Oral or parenteral steroids (≤3 months before the Screening Visit). Inhaled and topical steroids are allowed.
28. SYSADOA (e.g. glucosamine, chondroitin sulfate, or others), unless
administration of the same product (brand and dosage) is stable for at least 3 months prior to Screening Visit.
29. Other prohibited medications (unless the patient can suspend therapy for the duration of the study)
30. For women of childbearing potential: Pregnancy (i.e. positive pregnancy test at screening) or lactation
31. For women of childbearing potential: Failure to agree to practice adequate contraception methods (e.g. oral contraceptives, intra-uterine device (IUD), transdermal contraceptive patch).
32. Fertile men who do not agree to abstain from intercourse or to use a condom.
33. Any other condition that, in the opinion of the Investigator, may jeopardize the study conduct according to the protocol.

E.5 End points

E.5.1

Primary end point(s)

Mean change from baseline (randomization) in the WOMAC Pain Subscale score (normalized to 0-100 scores) at the end of the double blind treatment period.

E.5.1.1

Timepoint(s) of evaluation of this end point

The primary endpoint will be evaluated after 2 weeks of treatment

E.5.2

Secondary end point(s)

− Mean change from baseline in the WOMAC Pain Subscale score (normalized to 0-100 scores) at week 1.
− Mean change from baseline in the first question of the WOMAC Pain Subscale score (normalized to 0-100 scores) at week 1 and 2.
− Mean change from baseline in the WOMAC Stiffness Subscale score (normalized to 0-100 scores) at week 1 and 2.
− Mean change from baseline in the WOMAC Physical Function Subscale score (normalized to 0-100 scores) at week 1 and 2.
− Mean change from baseline in the WOMAC Total Index score (normalized to 0-100 scores) at week 1 and 2.
− Mean change from baseline in the severity of daily knee pain (separately for right and left knee), as measured by the 11-point NRS, at weeks 1 and 2.
− Number of patients reporting from baseline a knee pain reduction of at least 30%, i.e. a 30% decrease in the daily knee pain (separately for right and left knee) as measured by the 11-point NRS, at week 1 and 2.
− Mean change from baseline in the Patient’s Global Assessment of his/her arthritis at weeks 1 and 2.
− Mean change from baseline in the time needed to perform the 40 meters walking test at week 1 and 2.
− Mean change from baseline in the severity of knee pain (separately for right and left knee), as measured by 11-point NRS, after the completion of the 40 meters walking test at week 1 and 2.
− Number of responder patients according to the OARSI-OMERACT Response Criteria (Pham et al, 2004) at week 1 and 2. This set of response criteria will be applied in the present study considering the WOMAC Pain Subscale, the Patient’s Global Assessment of Arthritis and the WOMAC Physical Function subscale at week 1 and 2.
− Number of patients using rescue medication at week 1 and 2.

E.5.2.1

Timepoint(s) of evaluation of this end point

Secondary endpoints will be evaluated after 1 and 2 weeks of treatment.

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

Yes

E.6.13.1

Other scope of the trial description

Tolerability

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

E.8.6.2

Trial being conducted completely outside of the EEA

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:

200

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

224

F.4.2.2

In the whole clinical trial

224

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

2015-07-06

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2015-08-19

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2016-07-05

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