Clinical Trials Register

Summary
EudraCT Number:	2017-004655-23
Sponsor's Protocol Code Number:	CR4056-2-03
National Competent Authority:	Poland - Office for Medicinal Products
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2018-07-05
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

Poland - Office for Medicinal Products

A.2

EudraCT number

2017-004655-23

A.3

Full title of the trial

A randomized, double-blind, active- and placebo-controlled, parallel group, single dose, multicentre study to assess the analgesic effect of CR4056 in postoperative dental pain

A.3.1

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

Randomized, double-blind study evaluating the effect of a single dose of CR4056 in postoperative dental pain compared with placebo or another active treatment

A.4.1

Sponsor's protocol code number

CR4056-2-03

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	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	Senior 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	00390399066055
B.5.5	Fax number	00390399066161
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 150 mg
D.3.2	Product code	CR4056
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	N02
D.3.9.1	CAS number	1004997-71-0
D.3.9.2	Current sponsor code	CR4056
D.3.9.3	Other descriptive name	Quinazoline, 6-(1H-imidazol-1-yl)-2-phenyl-
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	150
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 100 mg
D.3.2	Product code	CR4056
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	N02
D.3.9.1	CAS number	1004997-71-0
D.3.9.2	Current sponsor code	CR4056
D.3.9.3	Other descriptive name	Quinazoline, 6-(1H-imidazol-1-yl)-2-phenyl-
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: 3
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 hard capsule
D.2.1.1.2	Name of the Marketing Authorisation holder	Pharma PFE GmbH
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.3.4	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	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, 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

Postoperative dental pain

E.1.1.1

Medical condition in easily understood language

Pain after extraction of a third molar

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	20.0
E.1.2	Level	PT
E.1.2	Classification code	10036276
E.1.2	Term	Postoperative analgesia
E.1.2	System Organ Class	10042613 - Surgical and medical procedures

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 analgesic efficacy of a single dose of CR4056 in patients with postoperative dental pain

E.2.2

Secondary objectives of the trial

To assess the safety and tolerability of a single dose of CR4056 in patients with postoperative dental pain

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 ≥18 and ≤65 years, in good health as determined by past medical history, physical examination, vital signs, ECG and laboratory tests.
3. Body Mass Index>18.5 and ≤35 kg/m2.
4. Planned elective dental surgical procedure consisting in the extraction of a mandibular third molar with partial or complete bone impaction (with Class II or III, position B or C using Pell and Gregor classification as confirmed by presurgery x-ray available in the patient file as source data). Concomitant extraction of the ipsilateral maxillary third molar is also accepted (while concomitant extractions of any contralateral tooth or any other dental surgical procedure is NOT accepted).
5. Willingness and capability to comply with the scheduled study visits, treatment plan and study procedures (e.g. completion of the e-diary).

E.4

Principal exclusion criteria

1. History of cardiovascular or cerebrovascular disease or presence of known significant risk factors for cardiovascular events.
2. History/known presence of coagulation or hematopoietic disease.
3. History/known presence of gastric/duodenal ulcers, gastrointestinal bleeding and inflammatory bowel diseases.
4. History/known presence or family history of malignant hyperthermia or anaesthesia-related events.
5. History of hypersensitivity to sulphonamides or other drugs.
6. Known allergy/hypersensitivity to the study drugs, or to any of their excipients.
7. History/known presence of hereditary problems of galactose intolerance, Lapp lactase deficiency or glucose-galactose malabsorption (the study drugs contain lactose).
8. History of alcohol or drug (including analgesics) abuse ≤12 months before the screening visit.
9. Known surgical or medical condition of the GI, hepatic, or renal system that might significantly alter the absorption, distribution, or excretion of any drug substance.
10. Any other known clinically relevant disease that, in the opinion of the Investigator, may jeopardize efficacy or safety assessments or may compromise the patient’s safety during trial participation.
11. 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.
12. Creatinine clearance <30 ml/min.
13. Any other laboratory examination performed at screening with clinically relevant findings, as judged by the Investigator.
14. 12-lead ECG with clinically relevant findings, as judged by the Investigator.
15. Contraindications for use of single dose celecoxib (see Celebrex® SmPC).
16. Contraindications for use of paracetamol (see Tachipirina® SmPC).
17. Use of drugs active on Central Nervous System (CNS) that cannot be withhold at least 7 days before randomization and until 24 h after the administration of the study drug.
18. Use of antithrombotic drugs, such as acetyl salicylic acid (oral doses ≤325 mg/day) or of other antiplatelet/anticoagulant drugs (including warfarin, heparin, rivaroxaban, and dabigatran) for the primary and secondary prevention of cardiovascular events that cannot be withhold at least 7 days before randomization and until 24 h after the administration of the study drug.
19. Use of drugs interacting with CYP450 enzymes that cannot be withhold at least 7 days before randomization and until 24 h after the administration of the study drug.
20. Use of other investigational drugs within 30 days or 5 half-lives, whichever is longer, before screening.
21. Difficulty in swallowing capsules/tablets.
22. Pregnant or lactating women.
23. Women of childbearing potential who do not agree to practice an effective method of contraception from the enrolment up to 30 days after Investigational Medicinal Product (IMP) intake.
24. Fertile men with a female partner of childbearing potential who do not agree to use a condom from the enrolment up to 7 days after the IMP intake.
25. 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)

Summed, time-weighted Pain Intensity Difference (SPID) over 8 h after study drug administration (SPID8) using the 4-point categorical scale

E.5.1.1

Timepoint(s) of evaluation of this end point

Over 8 h after study drug administration

E.5.2

Secondary end point(s)

1. Summed time-weighted Pain Intensity Difference (SPID) using the 4-point categorical scale
2. SPID using the 100 mm VAS
3. TOTal PAin Relief (TOTPAR)
4. Pain Intensity Difference (PID) using both the 4-point categorical scale and the 100 mm VAS
5. Pain relief (PR)
6. Summed, time-weighted PRID (sum of PID and PR scores) (SPRID) using the categorical scales
7. Patient’s Global Evaluation of the study drug
8. Onset of analgesia as time to Perceptible PR and time to Meaningful PR
9. Maximum PID (peak-PID) using both the 4-point categorical scale and the 100 mm VAS
10. Maximum PR
11. Percentage of patients taking rescue analgesic medication
12. Time-to-first rescue analgesic medication use
13. Safety

E.5.2.1

Timepoint(s) of evaluation of this end point

1. Over 4, 6, 12, 24 after study drug administration
2. Over 4, 6, 8, 12, 24 after study drug administration
3. Over 4, 6, 8, 12, 24 after study drug administration
4. at different time points up to 24 h post dose
5. at the different time points up to 24 h post-dose
6. Over 4, 6, 8, 12, 24 h post-dose
7. 24 after study drug administration
8. Over 24 after study drug administration
9. during the first 8 h post-dose
10. during the first 8 h post-dose
11. Over 24 after study drug administration
12. Over 24 after study drug administration
13. Over 24 after study drug administration

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)

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

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:

230

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

126

F.4.2

For a multinational trial

F.4.2.1

In the EEA

248

F.4.2.2

In the whole clinical trial

248

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)

Patient will be followed by dentist as clinical practice

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

2018-09-24

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2018-06-06

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2019-07-02

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