Safety and Tolerability After Four Weeks of Treatment With AZD1656 in Patients With Type 2 Diabetes

• Sponsor: AstraZeneca (Industry)
• Overall Status: Completed
• CT.gov ID: NCT00856908
• Collaborator: (none)
• Enrollment: 20
• Location: 1
• Arms: 2
• Duration (Months): 5.9
• Patients Per Site Per Month: 3.4

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 Insulin

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

Study Design

• Study Type: Interventional
• Actual Enrollment: 20 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 During Four Weeks in T2DM Subjects Treated With Insulin
• Study Start Date: Feb 1, 2009
• Actual Primary Completion Date: Aug 1, 2009
• Actual Study Completion Date: Aug 1, 2009

Arms and Interventions

Arm	Intervention/Treatment
Experimental: 1 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; Tolerable dose given twice daily
Placebo Comparator: 2 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; Tolerable dose given twice daily

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 following the morning dose 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 evening 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 an ANCOVA model, using treatment as fixed factor 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. Changes in percent have been obtained by subtraction by 100.

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 an ANCOVA model, using treatment as fixed factor 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. Changes in percent have been obtained by subtraction by 100

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 an ANCOVA model, using treatment as fixed factor 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. Changes in percent have been obtained by subtraction by 100.

Eligibility Criteria

Criteria

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

Inclusion Criteria:

• type II diabetes patients, female with non child-bearing potential

• Subjects with T2DM diagnosis for at least one year, treated with insulin alone or insulin in combination with other anti-diabetic drugs. Subjects must have been treated with insulin the last 3 months prior to enrolment (screening)

• HbA1c <11% at enrolment (screening) (HbA1c value according to international Diabetes Control and Complications Trial [DCCT] standard).

• FPG in the range of 7.0 to 13.0 mmol/L (126 to 234 mg/dL)

Exclusion Criteria:

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

• Use of glitazones, warfarin, amiodarone within 3 months prior to enrolment (screening) and use of potent CYP450 inhibitors, eg, ketoconazole and macrolide antibiotics within 14 days before randomisation.

• Any clinically significant abnormality identified on physical examination, laboratory tests or ECG, which in the judgment of the investigator would compromise the patients' safety or successful participation in the clinical study.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Research Site	Chula Vista	California	United States

Sponsors and Collaborators

• AstraZeneca

Investigators

• Study Director: Klas Malmberg, MD, PhD, Prof., AstraZeneca R&D Mölndal
• Principal Investigator: Marcus Hompesch, MD, Profil Institut for Clinical Research Inc.

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: AstraZeneca
• ClinicalTrials.gov Identifier: NCT00856908
• Other Study ID Numbers: D1020C00020
• First Posted: Mar 6, 2009
• Last Update Posted: Dec 6, 2012
• Last Verified: Nov 1, 2012

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

Study Results

Participant Flow

Arm/Group Title	Experimental	Placebo Comparator
Arm/Group Description	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	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
Period Title: Overall Study
STARTED	15	5
COMPLETED	14	5
NOT COMPLETED	1	0

Baseline Characteristics

Arm/Group Title	Experimental	Placebo Comparator	Total
Arm/Group Description	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	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	Total of all reporting groups
Overall Participants	15	5	20
Age (years) [Mean (Full Range) ]
Mean (Full Range) [years]	52.6	57.2	53.8
Sex: Female, Male (Count of Participants)
Female	9 60%	3 60%	12 60%
Male	6 40%	2 40%	8 40%

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 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	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
Measure Participants	14	5
Mean (Standard Deviation) [mmHg]	0.4 (8.5)	5.0 (6.4)

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 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	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
Measure Participants	14	5
Mean (Standard Deviation) [mmHg]	3.4 (7.6)	0.6 (2.9)

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 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	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
Measure Participants	14	5
Mean (Standard Deviation) [beats/min]	0.7 (4.4)	-5.4 (4.0)

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 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	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
Measure Participants	14	5
Mean (Standard Deviation) [kg]	-0.54 (1.65)	-1.32 (1.18)

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 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	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
Measure Participants	15	5
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 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
Measure Participants	14
Geometric Mean (95% Confidence Interval) [umol*h/L]	23.49

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 following the morning dose last day of treatment

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Experimental
Arm/Group Description	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
Measure Participants	14
Geometric Mean (95% Confidence Interval) [umol/L]	2.415

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 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
Measure Participants	14
Median (Full Range) [h]	0.500

9. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Experimental
Arm/Group Description	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
Measure Participants	13
Mean (Full Range) [h]	5.239

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 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
Measure Participants	14
Mean (Full Range) [L/h]	9.382

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 an ANCOVA model, using treatment as fixed factor 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. Changes in percent have been obtained by subtraction by 100.
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 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	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
Measure Participants	14	5
Least Squares Mean (95% Confidence Interval) [relative change in percent]	-7	4

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 an ANCOVA model, using treatment as fixed factor 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. Changes in percent have been obtained by subtraction by 100
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 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	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
Measure Participants	14	5
Least Squares Mean (95% Confidence Interval) [relative change in percent]	-2	-29

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 an ANCOVA model, using treatment as fixed factor 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. Changes in percent have been obtained by subtraction by 100.
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 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	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
Measure Participants	14	5
Least Squares Mean (95% Confidence Interval) [relative change in percent]	-4	-3

Adverse Events

Arm/Group Title	Experimental		Placebo Comparator
Arm/Group Description	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		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
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	0/15 (0%)		0/5 (0%)
Other (Not Including Serious) Adverse Events
	Experimental		Placebo Comparator
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	13/15 (86.7%)		3/5 (60%)
Gastrointestinal disorders
Abdominal Pain Upper	1/15 (6.7%)		0/5 (0%)
Diarrhoea	3/15 (20%)		2/5 (40%)
Constipation	1/15 (6.7%)		0/5 (0%)
Nausea	1/15 (6.7%)		1/5 (20%)
General disorders
Non-Cardiac Chest Pain	1/15 (6.7%)		0/5 (0%)
Pain	0/15 (0%)		1/5 (20%)
Infections and infestations
Upper Respiratory Tract Infection	0/15 (0%)		1/5 (20%)
Urinary Tract Infection	2/15 (13.3%)		1/5 (20%)
Injury, poisoning and procedural complications
Application Site Reaction	2/15 (13.3%)		0/5 (0%)
Catheter Site Pain	2/15 (13.3%)		0/5 (0%)
Investigations
Blood Glucose Decreased	2/15 (13.3%)		0/5 (0%)
Metabolism and nutrition disorders
Iron Deficiency Anaemia	0/15 (0%)		1/5 (20%)
Oedema Peripheral	1/15 (6.7%)		0/5 (0%)
Musculoskeletal and connective tissue disorders
Limb Discomfort	1/15 (6.7%)		0/5 (0%)
Pain In Extremity	4/15 (26.7%)		0/5 (0%)
Nervous system disorders
Headache	10/15 (66.7%)		1/5 (20%)
Restless Legs Syndrome	1/15 (6.7%)		0/5 (0%)
Respiratory, thoracic and mediastinal disorders
Oropharyngeal Pain	1/15 (6.7%)		0/5 (0%)
Rhinorrhoea	1/15 (6.7%)		0/5 (0%)
Vascular disorders
Ecchymosis	1/15 (6.7%)		0/5 (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.