Study to Assess the Safety and Tolerability After Multiple Oral Doses of AZD1656 in Patients With Type 2 Diabetes Mellitus Treated With Metformin

• Sponsor: AstraZeneca (Industry)
• Overall Status: Completed
• CT.gov ID: NCT00817778
• Collaborator: (none)
• Enrollment: 27
• Location: 1
• Arms: 2
• Duration (Months): 5.9
• Patients Per Site Per Month: 4.5

Study Details

Study Description

Brief Summary

The purpose of this study is to assess the 1 month safety and tolerability after multiple oral doses of AZD1656 in patients with Type 2 Diabetes Mellitus Treated with Metformin

Condition or Disease	Intervention/Treatment	Phase
Type 2 Diabetes	Drug: AZD1656; Drug: Placebo	Phase 2

Study Design

• Study Type: Interventional
• Actual Enrollment: 27 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Single (Participant)
• Primary Purpose: Treatment
• Official Title: A Randomised, Single-Blind, Placebo-Controlled, Phase IIA Study to Assess the Safety and Tolerability After Multiple Oral Doses of AZD1656 in Patients With Type 2 Diabetes Mellitus Treated With Metformin
• Study Start Date: Jan 1, 2009
• Actual Primary Completion Date: Jul 1, 2009
• Actual Study Completion Date: Jul 1, 2009

Arms and Interventions

Arm	Intervention/Treatment
Experimental: AZD1656 Dose titration of oral suspension during 4 days to a tolerable dose given twice daily. Subjects will thereafter be treated with this dose twice daily for another 24 days	Drug: AZD1656; Subjects will be treated with tolerable dose twice daily for another 24 days.
Placebo Comparator: Placebo Dose titration of oral suspension during 4 days to a tolerable dose given twice daily. Subjects will thereafter be treated with this dose twice daily for another 24 days	Drug: Placebo; Subjects will be treated with tolerable dose twice daily for another 24 days.

Outcome Measures

Primary Outcome Measures

1. Systolic Blood Pressure, Change From Baseline to End of Treatment [Baseline is pre-dose first day of dosing, end of treatment is the morning following the treatment period]

2. Diastolic Blood Pressure, Change From Baseline to End of Treatment [Baseline is pre-dose first day of dosing, end of treatment is the morning following the treatment period]

3. Pulse, Change From Baseline to End of Treatment [Baseline is pre-dose first day of dosing, end of treatment is the morning following the treatment period]

4. Weight, Change From Baseline to End of Treatment [Baseline is the day before first dose, end of treatment is last day of treatment]

5. Clinically Relevant Change of Laboratory Variables [Measured regularly from day before first dose to day after last dose]

   Number of participants with clinically relevant change of laboratory variables (clinical chemistry, haematology and urinalysis parameters

Secondary Outcome Measures

1. Area Under the Plasma Concentration vs Time Curve (AUC0-24) of AZD1656 [Measured last day of treatment]

   Dose-adjusted to a total daily dose of 100 mg due to titrated doses

2. Maximum Plasma Concentration of AZD1656 [Measured last day of treatment]

   Dose-adjusted to a morning dose of 50 mg due to titrated doses

3. Time to Reach Maximum Plasma Concentration of AZD1656 [Measured last day of treatment]

4. Terminal Elimination Half-life of AZD1656 [Measured following the afternoon dose last day of treatment]

5. Apparent Oral Clearance of AZD1656 [Measured last day of treatment]

6. P-Glucose (AUC0-24)/24, Change From Baseline to End of Treatment [Baseline is the day before first dose, end of treatment is last day of treatment]

   Log ratio (End of treatment/Baseline) has been analysed in a mixed-effect ANOVA model, using treatment as fixed effect and log(Baseline) as covariate. Resulting estimates have been back-transformed from the log-scale and then multiplied by 100 to obtain the relative ratio (end of treatment/placebo) in percent.

7. S-Insulin (AUC0-24)/24, Change From Baseline to End of Treatment [Baseline is the day before first dose, end of treatment is last day of treatment]

   Log ratio (End of treatment/Baseline) has been analysed in a mixed-effect ANOVA model, using treatment as fixed effect and log(Baseline) as covariate. Resulting estimates have been back-transformed from the log-scale and then multiplied by 100 to obtain the relative ratio (end of treatment/placebo) in percent.

8. S-C-Peptide (AUC0-24)/24, Change From Baseline to End of Treatment [Baseline is the day before first dose, end of treatment is last day of treatment]

   Log ratio (End of treatment/Baseline) has been analysed in a mixed-effect ANOVA model, using treatment as fixed effect and log(Baseline) as covariate. Resulting estimates have been back-transformed from the log-scale and then multiplied by 100 to obtain the relative ratio (end of treatment/placebo) in percent.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 30 Years to 75 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Male or women of non-childbearing potential (postmenopausal, and/or have undergone hysterectomy and/or bilateral oophorectomy or salpingectomy/ tubal ligation)

• Ongoing treatment with metformin on a stable dose of ≥ 1500 mg/day for at least 8 weeks prior to randomisation

• HbA1c ≤ 10% at enrolment (HbA1c value according to international Diabetes Control and Complications Trial [DCCT] standard)

Exclusion Criteria:

• History of ischemic heart disease, symptomatic heart failure, stroke, transitory ischemic attack or symptomatic peripheral vascular disease

• Clinically significant abnormalities in ECG, clinical chemistry, haematology, or urine analysis results. Positive test for Hepatitis B surface antigen or antibodies to human immunodeficiency virus (HIV) or antibodies to Hepatitis C virus

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Research Site	San Antonio	Texas	United States

Sponsors and Collaborators

• AstraZeneca

Investigators

• Study Director: Klas Malmberg, MD, PhD, Prof, AstraZeneca R&D Mölndal
• Principal Investigator: Emanuel P DeNoia, M.D, Healthcare Discoveries LLC Icon Development Solutions

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: AstraZeneca
• ClinicalTrials.gov Identifier: NCT00817778
• Other Study ID Numbers: D1020C00019
• First Posted: Jan 6, 2009
• Last Update Posted: Nov 16, 2012
• Last Verified: Oct 1, 2012

• Keywords provided by AstraZeneca: Type II Diabetes
• Additional relevant MeSH terms: Diabetes Mellitus; Diabetes Mellitus, Type 2

Study Results

Participant Flow

Arm/Group Title	Experimental	Placebo Comparator
Arm/Group Description	AZD1656	Placebo
Period Title: Overall Study
STARTED	19	8
COMPLETED	16	5
NOT COMPLETED	3	3

Baseline Characteristics

Arm/Group Title	Experimental	Placebo Comparator	Total
Arm/Group Description	AZD1656	Placebo	Total of all reporting groups
Overall Participants	19	8	27
Age (years) [Mean (Full Range) ]
Mean (Full Range) [years]	60.2	60.3	60.2
Sex: Female, Male (Count of Participants)
Female	6 31.6%	5 62.5%	11 40.7%
Male	13 68.4%	3 37.5%	16 59.3%

Outcome Measures

1. Primary Outcome

Title	Systolic Blood Pressure, Change From Baseline to End of Treatment
Time Frame	Baseline is pre-dose first day of dosing, end of treatment is the morning following the treatment period

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Experimental	Placebo Comparator
Arm/Group Description	AZD1656	Placebo
Measure Participants	16	5
Mean (Standard Deviation) [mmHg]	-0.5 (11.48)	9.2 (10.43)

2. Primary Outcome

Title	Diastolic Blood Pressure, Change From Baseline to End of Treatment
Time Frame	Baseline is pre-dose first day of dosing, end of treatment is the morning following the treatment period

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Experimental	Placebo Comparator
Arm/Group Description	AZD1656	Placebo
Measure Participants	16	5
Mean (Standard Deviation) [mmHg]	-0.2 (6.20)	2.0 (10.32)

3. Primary Outcome

Title	Pulse, Change From Baseline to End of Treatment
Time Frame	Baseline is pre-dose first day of dosing, end of treatment is the morning following the treatment period

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Experimental	Placebo Comparator
Arm/Group Description	AZD1656	Placebo
Measure Participants	16	5
Mean (Standard Deviation) [beats/min]	2.7 (5.69)	-1.6 (6.23)

4. Primary Outcome

Title	Weight, Change From Baseline to End of Treatment
Time Frame	Baseline is the day before first dose, end of treatment is last day of treatment

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Experimental	Placebo Comparator
Arm/Group Description	AZD1656	Placebo
Measure Participants	16	5
Mean (Standard Deviation) [kg]	0.2 (1.00)	0.0 (3.81)

5. Primary Outcome

Title	Clinically Relevant Change of Laboratory Variables
Description	Number of participants with clinically relevant change of laboratory variables (clinical chemistry, haematology and urinalysis parameters
Time Frame	Measured regularly from day before first dose to day after last dose

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Experimental	Placebo Comparator
Arm/Group Description	AZD1656	Placebo
Measure Participants	19	8
Number [Participants]	0 0%	0 0%

6. Secondary Outcome

Title	Area Under the Plasma Concentration vs Time Curve (AUC0-24) of AZD1656
Description	Dose-adjusted to a total daily dose of 100 mg due to titrated doses
Time Frame	Measured last day of treatment

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Experimental
Arm/Group Description	AZD1656
Measure Participants	16
Geometric Mean (Standard Deviation) [umol*h/L]	23.17 (7.46)

7. Secondary Outcome

Title	Maximum Plasma Concentration of AZD1656
Description	Dose-adjusted to a morning dose of 50 mg due to titrated doses
Time Frame	Measured last day of treatment

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Experimental
Arm/Group Description	AZD1656
Measure Participants	16
Geometric Mean (Standard Deviation) [umol/L]	1.90 (0.99)

8. Secondary Outcome

Title	Time to Reach Maximum Plasma Concentration of AZD1656
Time Frame	Measured last day of treatment

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Experimental
Arm/Group Description	AZD1656
Measure Participants	16
Median (Full Range) [h]	0.625

9. Secondary Outcome

Title	Terminal Elimination Half-life of AZD1656
Time Frame	Measured following the afternoon dose last day of treatment

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Experimental
Arm/Group Description	AZD1656
Measure Participants	10
Geometric Mean (Full Range) [h]	7.07

10. Secondary Outcome

Title	Apparent Oral Clearance of AZD1656
Time Frame	Measured last day of treatment

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Experimental
Arm/Group Description	AZD1656
Measure Participants	16
Geometric Mean (Full Range) [L/h]	9.02

11. Secondary Outcome

Title	P-Glucose (AUC0-24)/24, Change From Baseline to End of Treatment
Description	Log ratio (End of treatment/Baseline) has been analysed in a mixed-effect ANOVA model, using treatment as fixed effect and log(Baseline) as covariate. Resulting estimates have been back-transformed from the log-scale and then multiplied by 100 to obtain the relative ratio (end of treatment/placebo) in percent.
Time Frame	Baseline is the day before first dose, end of treatment is last day of treatment

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Experimental	Placebo Comparator
Arm/Group Description	AZD1656	Placebo
Measure Participants	16	5
Least Squares Mean (95% Confidence Interval) [Relative ratio in percent]	75.85	99.42

12. Secondary Outcome

Title	S-Insulin (AUC0-24)/24, Change From Baseline to End of Treatment
Description	Log ratio (End of treatment/Baseline) has been analysed in a mixed-effect ANOVA model, using treatment as fixed effect and log(Baseline) as covariate. Resulting estimates have been back-transformed from the log-scale and then multiplied by 100 to obtain the relative ratio (end of treatment/placebo) in percent.
Time Frame	Baseline is the day before first dose, end of treatment is last day of treatment

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Experimental	Placebo Comparator
Arm/Group Description	AZD1656	Placebo
Measure Participants	16	5
Least Squares Mean (95% Confidence Interval) [Relative ratio in percent]	103.81	86.06

13. Secondary Outcome

Title	S-C-Peptide (AUC0-24)/24, Change From Baseline to End of Treatment
Description	Log ratio (End of treatment/Baseline) has been analysed in a mixed-effect ANOVA model, using treatment as fixed effect and log(Baseline) as covariate. Resulting estimates have been back-transformed from the log-scale and then multiplied by 100 to obtain the relative ratio (end of treatment/placebo) in percent.
Time Frame	Baseline is the day before first dose, end of treatment is last day of treatment

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Experimental	Placebo Comparator
Arm/Group Description	AZD1656	Placebo
Measure Participants	16	5
Least Squares Mean (95% Confidence Interval) [Relative ratio in percent]	103.60	98.01

Adverse Events

Arm/Group Title	Experimental		Placebo Comparator
Arm/Group Description	AZD1656		Placebo
All Cause Mortality
	Experimental		Placebo Comparator
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Experimental		Placebo Comparator
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	1/19 (5.3%)		0/8 (0%)
Cardiac disorders
Rapid Atrial Fibrillation	1/19 (5.3%)		0/8 (0%)
Other (Not Including Serious) Adverse Events
	Experimental		Placebo Comparator
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	15/19 (78.9%)		7/8 (87.5%)
Cardiac disorders
Supraventricular Tachycardia	1/19 (5.3%)		0/8 (0%)
Supraventricular Tachycardia	1/19 (5.3%)		0/8 (0%)
Ear and labyrinth disorders
Vertigo Positional	0/19 (0%)		1/8 (12.5%)
Eye disorders
Vision Blurred	0/19 (0%)		1/8 (12.5%)
Gastrointestinal disorders
Constipation	1/19 (5.3%)		0/8 (0%)
Diarrhoea	1/19 (5.3%)		0/8 (0%)
Nausea	0/19 (0%)		1/8 (12.5%)
Toothache	1/19 (5.3%)		0/8 (0%)
General disorders
Fatigue	0/19 (0%)		1/8 (12.5%)
Infections and infestations
Hordeolum	0/19 (0%)		1/8 (12.5%)
Injury, poisoning and procedural complications
Excoriation	0/19 (0%)		1/8 (12.5%)
Skin Laceration	1/19 (5.3%)		0/8 (0%)
Blood Glucose Decreased	9/19 (47.4%)		1/8 (12.5%)
Musculoskeletal and connective tissue disorders
Costochondritis	0/19 (0%)		1/8 (12.5%)
Muscle Spasms	0/19 (0%)		1/8 (12.5%)
Nervous system disorders
Dizziness	1/19 (5.3%)		2/8 (25%)
Headache	4/19 (21.1%)		2/8 (25%)
Tremor	1/19 (5.3%)		0/8 (0%)
Respiratory, thoracic and mediastinal disorders
Rhinitis Allergic	1/19 (5.3%)		0/8 (0%)
Rhinorrhoea	1/19 (5.3%)		0/8 (0%)
Skin and subcutaneous tissue disorders
Erythema	1/19 (5.3%)		0/8 (0%)
Rash	1/19 (5.3%)		0/8 (0%)
Skin Irritation	1/19 (5.3%)		0/8 (0%)

Limitations/Caveats

The primary objective of the study was to assess safety and tolerability and hence the study was not sized based on statistical considerations. The most import outcome, "no safety or tolerability concerns were identified", is not a numerical variable

More Information

Certain Agreements

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

CONTRACT RESEARCH ORGANIZATION AGREEMENT by and between ASTRAZENECA AB and the CRO. CRO agrees that AstraZeneca shall have the exclusive right to publish the results of the Study, including all Work Product, and that such results may not be published or otherwise disseminated by CRO without the prior written approval of AstraZeneca.