Study to evaluate the Efficacy, Safety, Tolerability and Pharmacokinetics of AZD1386 in patients with Osteoarthritis (OA) of the knee - OA19

Study identifier:D5090C00019

ClinicalTrials.gov identifier:N/A

EudraCT identifier:N/A

CTIS identifier:N/A

Terminated/Withdrawn

Official Title

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

Medical condition

Pain

Phase

Phase 2

Healthy volunteers

Study drug

AZD1386, Placebo

Sex

All

Actual Enrollment

241

Study type

Interventional

Age

40 Years - 80 Years

Date

Study Start Date: 01 Mar 2009

Primary Completion Date: 01 Jul 2009

Study Completion Date: 01 Jul 2009

Study design

Allocation: Randomized
Endpoint Classification: Efficacy Study
Intervention Model: Parallel Assignment
Masking: Double Blind
Primary Purpose: Treatment

Verification:

Verified 01 May 2012 by AstraZeneca Pharmaceuticals

Collaborators

Inclusion and exclusion criteria

Location

Research Site

Pleven, Bulgaria

Location

Research Site

Sofia, Bulgaria

Location

Research Site

Bay Roberts, NL, Canada

Location

Research Site

St.Johns, NL, Canada

Location

Research Site

Halifax, NS, Canada

Location

Research Site

Brampton, ON, Canada

Location

Research Site

Etobicoke, ON, Canada

Location

Research Site

Hamilton, ON, Canada

Arms	Assigned Interventions
Experimental: AZD1386, 90 mg	Drug: AZD1386 oral, during 4 weeks
Experimental: AZD1386, 30 mg	Drug: AZD1386 oral, during 4 weeks
Placebo Comparator: Placebo	Drug: Placebo Oral, during 4 weeks

Participant Flow

Recruitment Details

Key information relevant to the recruitment process for the overall study, such as dates of the recruitment period and locations
International multi-center study, 41sites in North America, Japan and Europe recruited between March and July 2009. 327 participants enrolled into the study

Pre-Assignment Details

Significant events and approaches for the overall study following participant enrollment, but prior to group assignment
Patients with past or ongoing intolerability to NSAID´s/COX-2`s or paracetamol/acetaminophen or patients with insufficient pain relief from these treatments were included in the study. The WOMAC pain on walking had to be ≥40 mm and ≤90 mm on a Visual Analogue Scale (VAS) at both enrolment and after 1 weeks wash-out of medication (randomisation)

Reporting Groups

	Description
Experimental 90 mg	AZD1386 90 mg twice a day (bid) for 4 weeks
Experimental 30 mg	AZD1386 30 mg twice a day (bid) for 4 weeks
Placebo control	Placebo bid for 4 weeks

Participant Flow: Overall Study

	Experimental 90 mg	Experimental 30 mg	Placebo control
STARTED	104^[1]	44^[2]	93^[3]
Interim analysis	83^[4]	37^[5]	81^[6]
COMPLETED	87^[7]	37^[8]	85^[9]
NOT COMPLETED	17	7	8
Adverse Event	11	3	3
Lack of Efficacy	2	1	0
Withdrawal by Subject	2	1	2
Protocol Violation	0	0	1
Incorrect enrolment	1	2	0
Intake of prohibited concom. medication	0	0	1
Mis-randomisation of patient	1	0	0
Administrative	0	0	1

[1]	One of these patients did not receive study drug since incorrectly enrolled (mis-randomisation)
[2]
[3]
[4]
[5]
[6]
[7]
[8]
[9]

Baseline Characteristics

Analysis Population Description -- Explanation of how the number of participants for analysis was determined.

Reporting Groups

	Description
Experimental 90 mg	AZD1386 90 mg twice a day (bid) for 4 weeks
Experimental 30 mg	AZD1386 30 mg twice a day (bid) for 4 weeks
Placebo control	Placebo bid for 4 weeks

Baseline Measures

	Experimental 90 mg	Experimental 30 mg	Placebo control	Total
Number of Participants [units: Participants]	104	44	93	241
Age Continuous [units: Years] Median ( Full Range )	62 (40 to 79)	61 (40 to 79)	61 (40 to 79)	62 (40 to 79)
Gender, Male/Female [units: Participants]
Female	70	32	65	167
Male	34	12	28	74

Outcome Measures

1. Primary Outcome Measure: Mean of week 2 and week 4 changes from baseline in Western Ontario and McMaster Universities Arthritis Index (WOMAC) pain subscale, 48 hours recall. [ Time Frame: Baseline, week 2, week 4. ]

Measure Type	Primary
Measure Name	Mean of week 2 and week 4 changes from baseline in Western Ontario and McMaster Universities Arthritis Index (WOMAC) pain subscale, 48 hours recall.
Measure Description	The WOMAC pain subscale is a self-administered electronic scale with 5 questions (Walking on flat surface, Going up or down stairs, At night while in bed, Sitting or lying, Standing upright). Responses were recorded on a 50-mm line with 100 units. 0 mm indicated no pain and 50 mm indicated extreme pain. The scores were then converted to a 100-mm scale. WOMAC pain was derived by calculating the mean of the VAS scores from the 5 questions with score scale ranging from 0 to 100, 0 being no pain and 100 extreme pain.
Time Frame	Baseline, week 2, week 4.
Safety Issue?	No

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
Number of Participants Analyzed for the stated measure are defined according to the Modified Intention To Treat analysis set whereas numbers provided in the Participant Flow Module correspond to number of participants enrolled.

Reporting Groups

	Description
Experimental 90 mg	AZD1386 90 mg twice a day (bid) for 4 weeks
Experimental 30 mg	AZD1386 30 mg twice a day (bid) for 4 weeks
Placebo control	Placebo bid for 4 weeks

Measured Values

	Experimental 90 mg	Experimental 30 mg	Placebo control
Number of Participants Analyzed [units:participants]	99	42	90
Mean of week 2 and week 4 changes from baseline in Western Ontario and McMaster Universities Arthritis Index (WOMAC) pain subscale, 48 hours recall. [units: mm] Least Squares Mean (95% Confidence Interval)	-19.05 (-22.89 to -15.21)	-20.05 (-25.75 to -14.34)	-17.54 (-21.55 to -13.52)

No statistical analysis provided for Mean of week 2 and week 4 changes from baseline in Western Ontario and McMaster Universities Arthritis Index (WOMAC) pain subscale, 48 hours recall.

2. Secondary Outcome Measure: Mean of week 2 and week 4 changes from baseline in Western Ontario and McMaster Universities Arthritis Index (WOMAC) function subscale, 48 hours recall. [ Time Frame: Baseline, Week 2 and Week 4. ]

Measure Type	Secondary
Measure Name	Mean of week 2 and week 4 changes from baseline in Western Ontario and McMaster Universities Arthritis Index (WOMAC) function subscale, 48 hours recall.
Measure Description	The WOMAC VA 3.1. is a self-administered electronic questionnaire that assesses pain, stiffness and disability related to OA. The Function (daily activities) subscale consists of 17 questions. WOMAC function was derived by calculating the mean of the VAS scores from the 17 questions with scores ranging from 0 to 100, 0 = no difficulty in performing daily activities and 100 = extreme difficulty.
Time Frame	Baseline, Week 2 and Week 4.
Safety Issue?	No

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
Number of Participants Analyzed for the stated measure are defined according to the Modified Intention To Treat analysis set whereas numbers provided in the Participant Flow Module correspond to number of participants enrolled.

Reporting Groups

	Description
Experimental 90 mg	AZD1386 90 mg twice a day (bid) for 4 weeks
Experimental 30 mg	AZD1386 30 mg twice a day (bid) for 4 weeks
Placebo control	Placebo bid for 4 weeks

Measured Values

	Experimental 90 mg	Experimental 30 mg	Placebo control
Number of Participants Analyzed [units:participants]	99	42	90
Mean of week 2 and week 4 changes from baseline in Western Ontario and McMaster Universities Arthritis Index (WOMAC) function subscale, 48 hours recall. [units: mm] Least Squares Mean (95% Confidence Interval)	-17.19 (-21.17 to -13.21)	-18.84 (-24.66 to -13.01)	-17.12 (-21.29 to -12.96)

No statistical analysis provided for Mean of week 2 and week 4 changes from baseline in Western Ontario and McMaster Universities Arthritis Index (WOMAC) function subscale, 48 hours recall.

3. Secondary Outcome Measure: Mean of week 2 and week 4 changes from baseline in Western Ontario and McMaster Universities Arthritis Index (WOMAC) stiffness subscale, 48 hours recall. [ Time Frame: Baseline, Week 2 and Week 4. ]

Measure Type	Secondary
Measure Name	Mean of week 2 and week 4 changes from baseline in Western Ontario and McMaster Universities Arthritis Index (WOMAC) stiffness subscale, 48 hours recall.
Measure Description	The WOMAC VA3.1. is a self-administered questionnaire that assesses pain, stiffness and disability related to osteoarthritis. The Stiffness subscale consists of 2 questions (Severity of stiffness after first awakening in the morning and severity of stiffnes after periods of inactivity later in the day). WOMAC stiffness was derived by calculating the mean of the VAS scores from the 2 questions with score scale ranging from 0 to 100, 0 being no stiffness and 100 extreme stiffness.
Time Frame	Baseline, Week 2 and Week 4.
Safety Issue?	No

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
Number of Participants Analyzed for the stated measure are defined according to the Modified Intention To Treat analysis set whereas numbers provided in the Participant Flow Module correspond to number of participants enrolled.

Reporting Groups

	Description
Experimental 90 mg	AZD1386 90 mg twice a day (bid) for 4 weeks
Experimental 30 mg	AZD1386 30 mg twice a day (bid) for 4 weeks
Placebo control	Placebo bid for 4 weeks

Measured Values

	Experimental 90 mg	Experimental 30 mg	Placebo control
Number of Participants Analyzed [units:participants]	99	42	90
Mean of week 2 and week 4 changes from baseline in Western Ontario and McMaster Universities Arthritis Index (WOMAC) stiffness subscale, 48 hours recall. [units: mm] Least Squares Mean (95% Confidence Interval)	-16.05 (-20.19 to -11.91)	-17.49 (-23.62 to -11.37)	-17.48 (-21.82 to -13.14)

No statistical analysis provided for Mean of week 2 and week 4 changes from baseline in Western Ontario and McMaster Universities Arthritis Index (WOMAC) stiffness subscale, 48 hours recall.

4. Secondary Outcome Measure: Mean of week 2 and week 4 changes from baseline in Western Ontario and McMaster Universities Arthritis Index (WOMAC) total score, 48 hours recall [ Time Frame: Baseline, Week 2 and Week 4. ]

Measure Type	Secondary
Measure Name	Mean of week 2 and week 4 changes from baseline in Western Ontario and McMaster Universities Arthritis Index (WOMAC) total score, 48 hours recall
Measure Description	The WOMAC VA3.1. is a self-administered questionnaire that assesses pain, stiffness and disability related to osteoarthritis. It consists of a pain subscale (5 questions), function subscale (17 questions). and a stiffness subscale (2 questions). The total score was derived by calculating the mean of the VAS scores from all 24 questions with score scale ranging from 0 to 100, 0 being no pain, stiffness and difficulty in performing daily activities and 100 being extreme pain, stiffness and difficulty in performing daily activities.
Time Frame	Baseline, Week 2 and Week 4.
Safety Issue?	No

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
Number of Participants Analyzed for the stated measure are defined according to the Modified Intention To Treat analysis set whereas numbers provided in the Participant Flow Module correspond to number of participants enrolled.

Reporting Groups

	Description
Experimental 90 mg	AZD1386 90 mg twice a day (bid) for 4 weeks
Experimental 30 mg	AZD1386 30 mg twice a day (bid) for 4 weeks
Placebo control	Placebo bid for 4 weeks

Measured Values

	Experimental 90 mg	Experimental 30 mg	Placebo control
Number of Participants Analyzed [units:participants]	99	42	90
Mean of week 2 and week 4 changes from baseline in Western Ontario and McMaster Universities Arthritis Index (WOMAC) total score, 48 hours recall [units: mm] Least Squares Mean (95% Confidence Interval)	-17.48 (-21.35 to -13.61)	-18.93 (-24.63 to -13.24)	-17.27 (-21.33 to -13.22)

No statistical analysis provided for Mean of week 2 and week 4 changes from baseline in Western Ontario and McMaster Universities Arthritis Index (WOMAC) total score, 48 hours recall

Serious Adverse Events

Time Frame	No text entered.
Additional Description	One participant in the Experimental 90 mg Arm did not receive study drug since incorrectly enrolled and is therefore not included.

Reporting Groups

	Description
Experimental 90 mg	AZD1386 90 mg twice a day (bid) for 4 weeks
Experimental 30 mg	AZD1386 30 mg twice a day (bid) for 4 weeks
Placebo control	Placebo bid for 4 weeks

Serious Adverse Events

Experimental 90 mg

Experimental 30 mg

Placebo control

Total, serious adverse events

# participants affected / at risk

0/103 (0.00%)

1/44 (2.27%)

1/93 (1.08%)

Cardiac disorders

Acute Myocardial Infarction¹,^†

# participants affected / at risk

0/103 (0.00%)

0/44 (0.00%)

1/93 (1.08%)

Infections and infestations

Appendicitis¹,^†

# participants affected / at risk

0/103 (0.00%)

1/44 (2.27%)

0/93 (0.00%)

†	Events were collected by systematic assessment
1	Term from vocabulary, MedDRA 12.0
2	Term from vocabulary,

Other Adverse Events

Time Frame	No text entered.
Additional Description	One participant in the Experimental 90 mg Arm did not receive study drug since incorrectly enrolled and is therefore not included.

Frequency Threshold

Threshold above which other adverse events are reported	5%

Reporting Groups

	Description
Experimental 90 mg	AZD1386 90 mg twice a day (bid) for 4 weeks
Experimental 30 mg	AZD1386 30 mg twice a day (bid) for 4 weeks
Placebo control	Placebo bid for 4 weeks

Other Adverse Events

Experimental 90 mg

Experimental 30 mg

Placebo control

Total, other (not including serious) adverse events

# participants affected / at risk

61/103 (59.22%)

15/44 (34.09%)

14/93 (15.05%)

Nervous system disorders

Dysgeusia¹,^†

# participants affected / at risk

15/103 (14.56%)

2/44 (4.55%)

1/93 (1.08%)

Vascular disorders

Hot flush¹,^†

# participants affected / at risk

8/103 (7.77%)

5/44 (11.36%)

3/93 (3.23%)

Gastrointestinal disorders

Hypoaesthesia oral¹,^†

# participants affected / at risk

10/103 (9.71%)

2/44 (4.55%)

3/93 (3.23%)

Skin and subcutaneous tissue disorders

Hyperhidrosis¹,^†

# participants affected / at risk

8/103 (7.77%)

3/44 (6.82%)

0/93 (0.00%)

General disorders

Feeling cold¹,^†

# participants affected / at risk

7/103 (6.80%)

1/44 (2.27%)

1/93 (1.08%)

Nervous system disorders

Hypoaesthesia¹,^†

# participants affected / at risk

6/103 (5.83%)

1/44 (2.27%)

1/93 (1.08%)

Injury, poisoning and procedural complications

Thermal burn¹,^†

# participants affected / at risk

4/103 (3.88%)

3/44 (6.82%)

0/93 (0.00%)

Nervous system disorders

Headache¹,^†

# participants affected / at risk

3/103 (2.91%)

1/44 (2.27%)

5/93 (5.38%)

†	Events were collected by systematic assessment
1	Term from vocabulary, MedDRA 12.0
2	Term from vocabulary,

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.

The agreement is:

	The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is less than or equal to 60 days. The sponsor cannot require changes to the communication and cannot extend the embargo.
	The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is more than 60 days but less than or equal to 180 days . The sponsor cannot require changes to the communication and cannot extend the embargo.
	Other disclosure agreement that restricts the right of the PI to discuss or publish trial results after the trial is completed. Restriction Description:

Limitations and Caveats

Limitations of the study, such as early termination leading to small numbers of participants analyzed and technical problems with measurement leading to unreliable or uninterpretable data

Results Point of Contact

Name/Title:	Gerard Lynch
Organization:	AstraZeneca
Phone
E-mail:	[email protected]

Documents available

https://filehosting.pharmacm.com/DownloadService.ashx?client=CTR_MED_6111&studyid=368&filename=CSR-D5090C00019.pdf
Download
CSR-D5090C00019.pdf
Download
Trial Results Summaries
Available here

Contacts

Contact

AstraZeneca Clinical Study Information

800-236-9933

information.center@astrazeneca.com

Investigators

Principal Investigator

Richard L Leff

AZD1386AstraZeneca R&D Wilmington, USA

Sponsors

Collaborators

Inclusion Criteria

Exclusion Criteria

Research Site

Research Site

Research Site

Research Site

Research Site

Research Site

Research Site

Research Site

https://filehosting.pharmacm.com/DownloadService.ashx?client=CTR_MED_6111&studyid=368&filename=CSR-D5090C00019.pdf

CSR-D5090C00019.pdf

Trial Results Summaries