Clinical Trials Register

Summary
EudraCT Number:	2008-007797-37
Sponsor's Protocol Code Number:	D5090C00019
National Competent Authority:	Hungary - National Institute of Pharmacy
Clinical Trial Type:	EEA CTA
Trial Status:	Prematurely Ended
Date on which this record was first entered in the EudraCT database:	2009-01-27
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

2008-007797-37

A.3

Full title of the trial

A Phase II Randomised, Double-blind, Parallel Group, 4-week treatment, Adaptive Dose Finding, Multi-centre study evaluating the Efficacy, Safety, Tolerability and Pharmacokinetics of up to three different oral doses of AZD1386 and Placebo in patients with Osteoarthritis of the knee

A.4.1

Sponsor's protocol code number

D5090C00019

A.7

Trial is part of a Paediatric Investigation Plan

Information not present in EudraCT

A.8

EMA Decision number of Paediatric Investigation Plan

B. Sponsor Information
B.Sponsor: 1
B.1.1	Name of Sponsor	AstraZeneca AB
B.1.3.4	Country	Sweden
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
B.4.2	Country
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation
B.5.2	Functional name of contact point

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.3.2	Product code	AZD1386 30 mg
D.3.4	Pharmaceutical form	Capsule, hard
D.3.4.1	Specific paediatric formulation	Information not present in EudraCT
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	AZD1386 hydrogen sulphate
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	30
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)	Information not present in EudraCT
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	Information not present in EudraCT
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	Information not present in EudraCT
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	Information not present in EudraCT
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	Information not present in EudraCT
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	Information not present in EudraCT
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.3.2	Product code	AZD1386 10 mg
D.3.4	Pharmaceutical form	Capsule, hard
D.3.4.1	Specific paediatric formulation	Information not present in EudraCT
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	AZD1386 hydrogen sulphate
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	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)	Information not present in EudraCT
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	Information not present in EudraCT
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	Information not present in EudraCT
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	Information not present in EudraCT
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	Information not present in EudraCT
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	Information not present in EudraCT
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

Osteoarthritis of the knee

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	9.1
E.1.2	Level	LLT
E.1.2	Classification code	10023476
E.1.2	Term	Knee osteoarthritis

E.1.2 Medical condition or disease under investigation

E.1.2	Version	9.1
E.1.2	Level	LLT
E.1.2	Classification code	10031165
E.1.2	Term	Osteoarthritis knee

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 objectives are to evaluate the relationship between dose and analgesic efficacy of AZD1386 and evaluate the analgesic efficacy of AZD1386 in patients with osteoarthritis of the knee. The dependent variables will be mean of change from baseline to Week 2 (V4) and Week 4 (V5) in WOMAC pain subscale, 48 hours recall.

E.2.2

Secondary objectives of the trial

1. To evaluate the analgesic efficacy of AZD1386 during the night and day, in patients with osteoarthritis of the knee.

2. To evaluate the efficacy regarding function and stiffness and relationship between dose and efficacy of AZD1386 in patients with osteoarthritis of the knee.

3. To evaluate the percentage responders for AZD1386.

4. To investigate the safety and tolerability of AZD1386.

5. To evaluate the difference in use of rescue medication (paracetamol/acetaminophen) between AZD1386 and placebo.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1. Provision of informed consent prior to any study specific procedures.

2. Patients with OA of the knee that have unsatisfactory pain relief from past or on going nsNSAIDs/COX-2s and paracetamol/acetaminophen treatment either consecutively or simultaneously at recommended doses for at least 2 weeks, or with intolerability to past or on-going nsNSAIDs/COX-2s irrespective of doses, or dosing period, as judged by the investigator. Patients that have intolerability to NSAIDs/Cox-2s must have tried acetaminophen/paracetamol for at least 2 weeks at any time with unsatisfactory pain relief.

3. WOMAC pain on walking must be ≥40 mm and ≤90 mm VAS on both enrolment V1 and randomisation V2.

4. Male, or non-pregnant females, ≥40 and <80 years of age.

5.Symptomatic primary OA of the knee for at least 3 months prior to V1 according to the American College of Rheumatology (ACR).

6. Patients should belong to ACR global functional status class I, II or III (and should not be limited in their ability to perform usual self care i.e. not belong to class IV).

7. One knee should be designated as the target joint. The pain in the target joint must exceed pain experienced in other joints, and/or must exceed pain experienced from any concomitant medical condition.

8. OA in the target knee should be confirmed by X-ray at any time prior to randomisation, classified at least grade 2 according to Kellgren.

9. Women of child bearing potential are eligible for participation in the study if they have a negative pregnancy test at enrolment (V1) and at randomisation (V2), see Appendix D for further guidance.

10. Patients must be both willing and able to comply with and understand the study requirements

In addition, following criterion must be fulfilled for inclusion into the optional genetic research:
11. Provision of signed, written and dated informed consent for genetic research
If a patient declines to participate in the genetic component of the study, there will be no penalty or loss of benefit to the patient. The patient will not be excluded from other aspects of the study described in this clinical study protocol, so long as they consent.

E.4

Principal exclusion criteria

1. A current diagnosis of another form of arthritis, in addition to OA (e.g. rheumatoid arthritis, gout, septic arthritis, juvenile arthritis and lupus erythematosus) or wide spread chronic pain or fibromyalgia.

2. Patients with intra-articular or intramuscular corticosteroids or intra-articular hyaluronic acid injections within 3 months prior to randomisation.

3. Oral use of corticosteroids, barbiturates, rifampicin or phenytoin within 6 weeks prior to the randomisation visit.

4. Analgesic treatment, except low dose aspirin up to 325 mg/day for cerebrovascular and cardiovascular profylaxis.

5. Concomitant use of strong and moderate CYP3A4 enzyme inhibitors, such as ketoconazole, itraconazole, clarithromycin, nefazodone, erythromycin, fluconazole, aprepitant, diltiazem, verapamil, grapefruit juice, HIV protease inhibitors.

6. Within the last month prior the enrolment visit using >4 gram/ day (Japan: >1.5 gram/ day) of paracetamol/acetaminophen.

7. Within the last month prior the enrolment visit using more than the highest recommended dose of any NSAIDs or COX-2 inhibitors.

8. History, and/or presence, of somatic disease/condition, which may interfere with the objectives of the study as judged by the investigator.

9. Malabsorption, gastrointestinal disorder or surgery leading to impaired drug absorption.

10. History of malignancy, treated or untreated, within the past 5 years, with the exception of successfully treated basal cell or squamous cell carcinoma of the skin.

11. Risk factors for ventricular fibrillation e.g. family history of Short QT syndrome (SQTS) or sudden cardiac death (SCD) amongst first-degree relatives.

12. QTcF interval < 350 msec or > 450 msec at enrolment.

13. A recent history (in the past 3 months) suggestive of alcohol or drug abuse or dependence, including overuse/abuse of narcotics for management of pain.

14. Enrolment laboratory value for ALT, AST >2 times the upper limit of normal range.

15. Known positive test result for human immunodeficiency virus (HIV) antibody, hepatitis B surfactant antigen (HbsAg) or hepatitis C antibody.

16. Clinically significant abnormalities in clinical chemistry, haematology or urinalysis results as judged by the investigator.

17. Breast-feeding women.

18. Positive pregnancy test.

19. Donation of plasma within the two weeks prior to the enrolment visit and/or donation of blood within the three months prior to the enrolment visit and during the study.

20. History of allergic reaction to paracetamol/acetaminophen.

21. Involvement in the planning and conduct of the study (applies to both AZ staff and the staff at the study site).

22. Participation in another clinical trial, use of any investigational drugs or procedures or use of experimental medications within 30 days prior to the enrolment visit.

23. According to the investigator the patient should not participate in the study.

In addition, the following criteria are regarded as criteria for exclusion from the genetic research:

24. Previous bone marrow or stem cell transplant.

25. Whole blood transfusion within 120 days of the date of genetic sample collection.

E.5 End points

E.5.1

Primary end point(s)

Efficacy
Primary outcome variable:
- Change from baseline over time in WOMAC pain subscale, 48 hours recall.

Safety
- Change from baseline in physical examination, laboratory values, vital signs (blood pressure [BP], pulse rate and body temperature) and electrocardiogram (ECG) including QTcF.
- Adverse Events (AEs) including frequency and severity.
- AEs leading to withdrawals.

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

E.6.8

Bioequivalence

E.6.9

Dose response

Yes

E.6.10

Pharmacogenetic

Yes

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.8.3

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

Information not present in EudraCT

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

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

the last visit of the last patient undergoing the trial

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

F. Population of Trial Subjects
F.1 Age Range
F.1.1	Trial has subjects under 18	No
F.1.1.1	In Utero	No
F.1.1.2	Preterm newborn infants (up to gestational age < 37 weeks)	No
F.1.1.3	Newborns (0-27 days)	No
F.1.1.4	Infants and toddlers (28 days-23 months)	No
F.1.1.5	Children (2-11years)	No
F.1.1.6	Adolescents (12-17 years)	No
F.1.2	Adults (18-64 years)	Yes
F.1.3	Elderly (>=65 years)	Yes
F.2 Gender
F.2.1	Female	Yes
F.2.2	Male	Yes
F.3 Group of trial subjects
F.3.1	Healthy volunteers	No
F.3.2	Patients	Yes
F.3.3	Specific vulnerable populations	Yes
F.3.3.1	Women of childbearing potential not using contraception	No
F.3.3.2	Women of child-bearing potential using contraception	Yes
F.3.3.3	Pregnant women	No
F.3.3.4	Nursing women	No
F.3.3.5	Emergency situation	No
F.3.3.6	Subjects incapable of giving consent personally	No
F.3.3.7	Others	No
F.4 Planned number of subjects to be included
F.4.1	In the member state	60
F.4.2	For a multinational trial
F.4.2.1	In the EEA	310
F.4.2.2	In the whole clinical trial	520

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

2009-02-18

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2009-04-23

P. End of Trial
P.	End of Trial Status	Prematurely Ended
P.	Date of the global end of the trial	2000-07-14

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