A Study to Explore the Effects of Azilsartan Compared to Telmisartan on Insulin Resistance of Patients With Essential Hypertension on Type 2 Diabetes Mellitus by HOMA-R

• Sponsor: Takeda (Industry)
• Overall Status: Completed
• CT.gov ID: NCT02079805
• Collaborator: (none)
• Enrollment: 33
• Location: 1
• Arms: 2
• Duration (Months): 22
• Patients Per Site Per Month: 1.5

Study Details

Study Description

Brief Summary

Multicenter, randomized, open-label, parallel-group exploratory study to explore the effects of azilsartan (Azirva), compared with telmisartan, on insulin resistance in participants with essential hypertension complicated by type 2 diabetes mellitus

Condition or Disease	Intervention/Treatment	Phase
Essential Hypertension Complicated by Type 2 Diabetes Mellitus	Drug: Azilsartan; Drug: Telmisartan	Phase 4

Detailed Description

The primary objective of the present study is to explore the effects of azilsartan 20 mg, compared with telmisartan 40 mg, once daily orally for 12 weeks on insulin resistance in participants with essential hypertension complicated by type 2 diabetes mellitus.

Study Design

• Study Type: Interventional
• Actual Enrollment: 33 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Study to Explore the Effects of Azilsartan Compared to Telmisartan on Insulin Resistance of Patients With Essential Hypertension on Type 2 Diabetes Mellitus by HOMA-R
• Study Start Date: Jun 1, 2014
• Actual Primary Completion Date: Apr 1, 2016
• Actual Study Completion Date: Apr 1, 2016

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Azilsartan 20 mg Participants will receive azilsartan 20 mg once daily in the morning before or after breakfast.	Drug: Azilsartan; Azilsartan tablets; Other Names: Azilva Tablets
Active Comparator: Telmisartan 40 mg Participants will receive telmisartan 40 mg once daily in the morning before or after breakfast.	Drug: Telmisartan; Telmisartan tablets; Other Names: Micardis Tablets

Outcome Measures

Primary Outcome Measures

1. Change in Insulin Resistance Index (HOMA-R) From Baseline at the End of the Treatment Period (Week 12) [Baseline and Week 12]

   Change from the start of the treatment period (baseline) at the end of the treatment period (Week 12) was reported. Insulin Resistance Index (HOMA-R) measures insulin resistance, calculated by fasting insulin (μU/mL) multiplied by fasting glucose (mg/dL), and divided by a constant (405).

Secondary Outcome Measures

1. Change in Fasting Blood Glucose From Baseline at the End of the Treatment Period (Week 12) [Baseline and Week 12]

   Change from baseline in fasting blood glucose values collected at week 12 or final visit relative to baseline was reported.

2. Change in Fasting Insulin From Baseline at the End of the Treatment Period (Week 12) [Baseline and Week 12]

   Change from baseline in fasting insulin values collected at week 12 or final visit relative to baseline was reported.

3. Change in Glycosylated Hemoglobin (HbA1c) From Baseline at the End of the Treatment Period (Week 12) [Baseline and Week 12]

   Change from baseline in the values of glycosylated hemoglobin (the concentration of glucose bound to hemoglobin as a percent of the absolute maximum that can be bound) collected at week 12 or final visit relative to baseline was reported.

4. Change in Homeostasis Model Assessment of Beta Cell Function (HOMA-β) From Baseline at the End of the Treatment Period (Week 12) [Baseline and Week 12]

   Change from baseline in HOMA-β collected at week 12 or final visit relative to baseline was reported. Homeostasis model assessment of beta cell function measures as following; HOMA-β = fasting insulin (μU/mL) ×360/{fasting glucose (mg/dL) - 63}.

5. Change in 1,5-anhydroglucitol (1,5-AG) From Baseline at the End of the Treatment Period (Week 12) [Baseline and Week 12]

   Change from baseline in 1,5-G concentration collected at week 12 or final visit relative to baseline was reported.

6. Number of Participants With Treatment-Emergent Adverse Events [Up to Week 12]

Eligibility Criteria

Criteria

• Ages Eligible for Study: 20 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

1. The participant was given the diagnosis of grade I or II essential hypertension and was judged by the principal investigator or investigator that they can be appropriately treated with azilsartan 20 mg and telmisartan 40 mg.

2. Sitting systolic blood pressure of ≥ 130 mmHg and < 180 mmHg or sitting diastolic blood pressure of ≥ 80 mmHg and < 110 mmHg at the start of the treatment period (Week

1. Sitting blood pressure will be measured until 2 consecutive stable measurements are obtained (i.e., the difference between 2 measurements: diastolic blood pressure of <5 mmHg and systolic blood pressure of < 10 mmHg) after resting in a sitting position for at least 5 minutes. The average value of the last 2 measurements will be recorded (the first the decimal place is rounded off).

1. Type 2 diabetes mellitus

2. HbA1c (NGSP (National Glycohemoglobin Standardization Program) value) of < 8.4% during 3 months before informed consent, with a ≤ 0.3% change in HbA1c (peak minus nadir) during 3 months before informed consent

3. No change in diet/exercise therapy during the 3 months before the informed consent in a participant who has been on diet/exercise therapy and instructed to improve life style (e.g., diet and exercise)

4. Age ≥ 20 years at the time of consent

5. Outpatients

6. Capable of providing written consent before participation in this study.

Exclusion Criteria:

1. Grade III essential hypertension (i.e., sitting systolic blood pressure 180 mmHg or sitting diastolic blood pressure ≥ 110 mmHg), secondary hypertension, or malignant hypertension.

2. Grade II essential hypertension (i.e., sitting systolic blood pressure ≥ 160 mmHg or sitting diastolic blood pressure ≥ 100 mmHg) for which antihypertensive drug(s) are used

3. Use of oral antihypertensive medication within 2 weeks before the start of the treatment period Participants who are on any antihypertensive agent at the time of informed consent can be enrolled in the study only after 2-week washout following informed consent.

4. Use of RAS inhibitors or thiazolidines within 3 months before the start of the treatment period

5. Type 1 diabetes mellitus

6. Fasting blood glucose of < 180 mg/dL and HOMA-R of ≤ 1.6 at the start of the treatment period (Week 0)

7. Receiving or requiring any of the following at the time of informed consent:

• Insulin, glucagon-like peptide-1 (GLP-1) receptor agonists, or other parenteral hypoglycemic agents

• Combination therapy with 3 or more oral hypoglycemic agents

1. Change of antidiabetic medication (including dosage change) within 3 months before the start of the treatment period

2. Having diagnosed/treated any of the following cardiovascular diseases within 3 months before the start of the treatment period:

• Cardiac disease/condition: myocardial infarction, coronary revascularization procedure

• Cerebrovascular disease: cerebral infarction, cerebral haemorrhage, transient ischaemic attack

• Advanced hypertensive retinopathy (retinal bleeding or oozing, papilloedema)

1. Having diagnosed/treated for any of the following cardiovascular diseases more than 3 months before the start of the treatment period, and is now still in unstable condition.

• Cardiac disease/condition: myocardial infarction, coronary revascularization procedure

• Cerebrovascular disease: cerebral infarction, cerebral haemorrhage, transient ischaemic attack

1. Past or current history of any of the following cardiovascular diseases.

• Cardiac valve stenosis

• Angina pectoris requiring medication

• Congestive cardiac failure requiring medication

• Arrhythmia requiring medication (e.g., paroxysmal atrial fibrillation, severe bradycardia, torsade de pointes, and ventricular fibrillation)

• Arteriosclerosis obliterans with intermittent claudication or other symptoms

1. Have severe ketosis, diabetic coma or precoma, severe infection, or serious trauma

2. Clinically evident renal disorder (e.g., eGFR <30 mL/min/1.73 m2)

3. Markedly low bile secretion or severe hepatic disorder

4. History of hypersensitivity or allergy to azilsartan or telmisartan or to both.

5. Presence of hyperkalemia (potassium level ≥ 5.5 mEq/L on laboratory testing)

6. Currently participating in any other clinical study.

7. Pregnant women, women with possible pregnancy, or breast-feeding women.

8. Other participants who are inappropriate for participation in this study in the opinion of the principal investigator or investigator.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1		Kyoto-Shi	Kyoto	Japan

Sponsors and Collaborators

• Takeda

Investigators

• Study Director: General Manager, Takeda

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Takeda
• ClinicalTrials.gov Identifier: NCT02079805
• Other Study ID Numbers: 279/NRP-001; U1111-1151-7168; AZI-P4-004; JapicCTI-142461
• First Posted: Mar 6, 2014
• Last Update Posted: Aug 2, 2017
• Last Verified: Apr 1, 2017

• Additional relevant MeSH terms: Hypertension; Essential Hypertension; Diabetes Mellitus; Diabetes Mellitus, Type 2; Insulin Resistance; Telmisartan; Azilsartan medoxomil

Study Results

Participant Flow

Recruitment Details	Participants took part in the study at 27 investigative sites in Japan, from 04 June 2014 to 25 April 2016.
Pre-assignment Detail	Participants with diagnosis of type 2 diabetes mellitus were enrolled in 2 treatment group: Azilsartan 20 mg, and Telmisartan 40 mg for 12 weeks as treatment period.

Arm/Group Title	Telmisartan 40 mg	Azilsartan 20 mg
Arm/Group Description	Participants received telmisartan 40 mg, once daily in the morning before or after breakfast for 12 weeks as treatment priod.	Participants received azilsartan 20 mg, once daily in the morning before or after breakfast for 12 weeks as treatment priod.
Period Title: Overall Study
STARTED	16	17
COMPLETED	16	15
NOT COMPLETED	0	2

Baseline Characteristics

Arm/Group Title	Telmisartan 40 mg	Azilsartan 20 mg	Total
Arm/Group Description	Participants received telmisartan 40 mg, once daily in the morning before or after breakfast for 12 weeks as treatment priod.	Participants received azilsartan 20 mg, once daily in the morning before or after breakfast for 12 weeks as treatment priod.	Total of all reporting groups
Overall Participants	16	17	33
Age (Years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Years]	65.3 (9.10)	63.2 (12.76)	64.2 (11.02)
Sex: Female, Male (Count of Participants)
Female	9 56.3%	10 58.8%	19 57.6%
Male	7 43.8%	7 41.2%	14 42.4%
Weight (kg) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [kg]	70.95 (16.689)	70.41 (14.878)	70.67 (15.534)
BMI (kg/m^2) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [kg/m^2]	27.18 (3.720)	27.19 (4.642)	27.19 (4.154)
Smoking Classification (participants) [Number]
Never smoked	8 50%	8 47.1%	16 48.5%
Current smoker	2 12.5%	3 17.6%	5 15.2%
Ex-smoker	6 37.5%	6 35.3%	12 36.4%
Alcohol Classification (participants) [Number]
Yes	6 37.5%	5 29.4%	11 33.3%
No	10 62.5%	12 70.6%	22 66.7%
Duration of Hypertention (Years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Years]	4.71 (4.391)	3.54 (4.392)	4.11 (4.363)
Duration of Diabetes Mellitus (Years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Years]	4.53 (4.279)	4.89 (5.039)	4.72 (4.617)
Taking Biguanides (participants) [Number]
Had taken	3 18.8%	4 23.5%	7 21.2%
Not had taken	13 81.3%	13 76.5%	26 78.8%
Insulin Resistance Index (HOMA-R) (HOMA-R Score) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [HOMA-R Score]	3.31 (1.366)	4.24 (1.843)	3.79 (1.671)
Blood Pressure Systolic Mean (mmHg) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [mmHg]	145.6 (9.91)	143.3 (9.28)	144.4 (9.51)
Blood Pressure Diastolic Mean (mmHg) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [mmHg]	89.3 (10.61)	88.8 (7.19)	89.0 (8.87)
Glycosylated Hemoglobin (HbA1c) (percent) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [percent]	6.63 (0.411)	6.81 (0.488)	6.72 (0.454)

Outcome Measures

1. Primary Outcome

Title	Change in Insulin Resistance Index (HOMA-R) From Baseline at the End of the Treatment Period (Week 12)
Description	Change from the start of the treatment period (baseline) at the end of the treatment period (Week 12) was reported. Insulin Resistance Index (HOMA-R) measures insulin resistance, calculated by fasting insulin (μU/mL) multiplied by fasting glucose (mg/dL), and divided by a constant (405).
Time Frame	Baseline and Week 12

Outcome Measure Data

Analysis Population Description

The full analysis set was defined as the participants who received at least 1 dose of the study drug for the treatment period.

Arm/Group Title	Telmisartan 40 mg	Azilsartan 20 mg
Arm/Group Description	Participants received telmisartan 40 mg, once daily in the morning before or after breakfast for 12 weeks as treatment priod.	Participants received azilsartan 20 mg, once daily in the morning before or after breakfast for 12 weeks as treatment priod.
Measure Participants	16	16
Mean (Standard Deviation) [HOMA-R Score]	-0.23 (0.928)	0.22 (2.449)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Telmisartan 40 mg, Azilsartan 20 mg
	Comments	Telmisartan 40 mg, Azilsartan 20 mg
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.44
	Confidence Interval	(2-Sided) 95%; -0.89 to 1.78
	Parameter Dispersion	Type: Value:
	Estimation Comments

2. Secondary Outcome

Title	Change in Fasting Blood Glucose From Baseline at the End of the Treatment Period (Week 12)
Description	Change from baseline in fasting blood glucose values collected at week 12 or final visit relative to baseline was reported.
Time Frame	Baseline and Week 12

Outcome Measure Data

Analysis Population Description

The full analysis set was defined as the participants who received at least 1 dose of the study drug for the treatment period.

Arm/Group Title	Telmisartan 40 mg	Azilsartan 20 mg
Arm/Group Description	Participants received telmisartan 40 mg, once daily in the morning before or after breakfast for 12 weeks as treatment priod.	Participants received azilsartan 20 mg, once daily in the morning before or after breakfast for 12 weeks as treatment priod.
Measure Participants	16	16
Mean (Standard Deviation) [mg/dL]	-1.06 (14.991)	2.00 (18.308)

3. Secondary Outcome

Title	Change in Fasting Insulin From Baseline at the End of the Treatment Period (Week 12)
Description	Change from baseline in fasting insulin values collected at week 12 or final visit relative to baseline was reported.
Time Frame	Baseline and Week 12

Outcome Measure Data

Analysis Population Description

The full analysis set was defined as the participants who received at least 1 dose of the study drug for the treatment period.

Arm/Group Title	Telmisartan 40 mg	Azilsartan 20 mg
Arm/Group Description	Participants received telmisartan 40 mg, once daily in the morning before or after breakfast for 12 weeks as treatment priod.	Participants received azilsartan 20 mg, once daily in the morning before or after breakfast for 12 weeks as treatment priod.
Measure Participants	16	16
Mean (Standard Deviation) [µU/mL]	-0.818 (2.7623)	0.475 (6.3847)

4. Secondary Outcome

Title	Change in Glycosylated Hemoglobin (HbA1c) From Baseline at the End of the Treatment Period (Week 12)
Description	Change from baseline in the values of glycosylated hemoglobin (the concentration of glucose bound to hemoglobin as a percent of the absolute maximum that can be bound) collected at week 12 or final visit relative to baseline was reported.
Time Frame	Baseline and Week 12

Outcome Measure Data

Analysis Population Description

The full analysis set was defined as the participants who received at least 1 dose of the study drug for the treatment period.

Arm/Group Title	Telmisartan 40 mg	Azilsartan 20 mg
Arm/Group Description	Participants received telmisartan 40 mg, once daily in the morning before or after breakfast for 12 weeks as treatment priod.	Participants received azilsartan 20 mg, once daily in the morning before or after breakfast for 12 weeks as treatment priod.
Measure Participants	16	17
Mean (Standard Deviation) [percent]	0.10 (0.290)	0.09 (0.382)

5. Secondary Outcome

Title	Change in Homeostasis Model Assessment of Beta Cell Function (HOMA-β) From Baseline at the End of the Treatment Period (Week 12)
Description	Change from baseline in HOMA-β collected at week 12 or final visit relative to baseline was reported. Homeostasis model assessment of beta cell function measures as following; HOMA-β = fasting insulin (μU/mL) ×360/{fasting glucose (mg/dL) - 63}.
Time Frame	Baseline and Week 12

Outcome Measure Data

Analysis Population Description

The full analysis set was defined as the participants who received at least 1 dose of the study drug for the treatment period.

Arm/Group Title	Telmisartan 40 mg	Azilsartan 20 mg
Arm/Group Description	Participants received telmisartan 40 mg, once daily in the morning before or after breakfast for 12 weeks as treatment priod.	Participants received azilsartan 20 mg, once daily in the morning before or after breakfast for 12 weeks as treatment priod.
Measure Participants	16	16
Mean (Standard Deviation) [percent]	-3.88 (20.151)	-0.44 (30.985)

6. Secondary Outcome

Title	Change in 1,5-anhydroglucitol (1,5-AG) From Baseline at the End of the Treatment Period (Week 12)
Description	Change from baseline in 1,5-G concentration collected at week 12 or final visit relative to baseline was reported.
Time Frame	Baseline and Week 12

Outcome Measure Data

Analysis Population Description

The full analysis set was defined as the participants who received at least 1 dose of the study drug for the treatment period.

Arm/Group Title	Telmisartan 40 mg	Azilsartan 20 mg
Arm/Group Description	Participants received telmisartan 40 mg, once daily in the morning before or after breakfast for 12 weeks as treatment priod.	Participants received azilsartan 20 mg, once daily in the morning before or after breakfast for 12 weeks as treatment priod.
Measure Participants	16	16
Mean (Standard Deviation) [μg/mL]	0.24 (2.143)	-0.66 (2.454)

7. Secondary Outcome

Title	Number of Participants With Treatment-Emergent Adverse Events
Time Frame	Up to Week 12

Outcome Measure Data

Analysis Population Description

The safety analysis set was defined as the participants who received at least 1 dose of the study drug for the treatment period.

Arm/Group Title	Telmisartan 40 mg	Azilsartan 20 mg
Arm/Group Description	Participants received telmisartan 40 mg, once daily in the morning before or after breakfast for 12 weeks as treatment priod.	Participants received azilsartan 20 mg, once daily in the morning before or after breakfast for 12 weeks as treatment priod.
Measure Participants	16	17
Number [participants]	8 50%	6 35.3%

Adverse Events

Time Frame	Up to Week 12
Adverse Event Reporting Description	At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.
Arm/Group Title	Telmisartan 40 mg		Azilsartan 20 mg
Arm/Group Description	Participants received telmisartan 40 mg, once daily in the morning before or after breakfast for 12 weeks as treatment priod.		Participants received azilsartan 20 mg, once daily in the morning before or after breakfast for 12 weeks as treatment priod.
All Cause Mortality
	Telmisartan 40 mg		Azilsartan 20 mg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Telmisartan 40 mg		Azilsartan 20 mg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/16 (0%)		0/17 (0%)
Other (Not Including Serious) Adverse Events
	Telmisartan 40 mg		Azilsartan 20 mg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	8/16 (50%)		6/17 (35.3%)
Eye disorders
Diabetic retinopathy	0/16 (0%)		1/17 (5.9%)
Gastrointestinal disorders
Abdominal pain lower	1/16 (6.3%)		0/17 (0%)
General disorders
Chest discomfort	1/16 (6.3%)		0/17 (0%)
Infections and infestations
Nasopharyngitis	2/16 (12.5%)		2/17 (11.8%)
Bronchitis	1/16 (6.3%)		0/17 (0%)
Influenza	1/16 (6.3%)		0/17 (0%)
Investigations
Blood pressure decreased	0/16 (0%)		1/17 (5.9%)
Metabolism and nutrition disorders
Diabetes mellitus	1/16 (6.3%)		0/17 (0%)
Musculoskeletal and connective tissue disorders
Back pain	1/16 (6.3%)		1/17 (5.9%)
Spinal osteoarthritis	0/16 (0%)		1/17 (5.9%)
Reproductive system and breast disorders
Vaginal haemorrhage	1/16 (6.3%)		0/17 (0%)
Skin and subcutaneous tissue disorders
Cutaneous amyloidosis	1/16 (6.3%)		0/17 (0%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

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

The first study related publication will be a multi-center publication submitted within 24 months after conclusion or termination of a study at all sites. After such multi site publication, all proposed site publications and presentations will be submitted to sponsor for review 60 days in advance of publication. Site will remove Sponsor confidential information unrelated to study results. Sponsor can delay a proposed publication for another 60 days to preserve intellectual property.