Assessment of Renin Inhibition on Insulin Sensitivity, Diastolic Function and Aortic Compliance

• Sponsor: Brigham and Women's Hospital (Other)
• Overall Status: Terminated
• CT.gov ID: NCT01252238
• Collaborator: (none)
• Enrollment: 24
• Location: 1
• Arms: 3
• Duration (Months): 30
• Patients Per Site Per Month: 0.8

Study Details

Study Description

Brief Summary

This study is an investigation of the effect of commonly prescribed anti-hypertensive agents on insulin sensitivity, diastolic function and aortic compliance. The aims of the study are as follows:

Specific Aim 1: To determine in insulin resistant, hypertensive subjects if renin inhibition for 12 weeks modifies glucose homeostasis and insulin sensitivity.

To accomplish this specific aim, we will use three approaches: a fasting HOMA Index; and a three hour glucose tolerance test. Only hypertensive subjects with insulin resistance, as assessed by HOMA index will be enrolled in the study. Insulin resistance will be assessed basally and after twelve weeks of treatment with either a calcium channel blocker with placebo, or calcium channel blocker with a renin inhibitor, or a calcium channel blocker with a renin inhibitor and an angiotensin receptor antagonist.

Specific Aim 2: To determine in insulin resistant, hypertensive subjects if renin inhibition for 12 weeks modifies diastolic function and aortic compliance response to dietary sodium intake.

The same protocol and subjects will be used as defined in Specific Aim 1. Myocardial relaxation velocity (tissue Doppler imaging at the mitral annulus) and aortic compliance (characteristic aortic impedance) will be measured at baseline and then after acute and chronic renin inhibition:

1. Acute effect of renin inhibition: Hemodynamic measurements will be obtained on both high and low dietary sodium intake conditions (~1 week each) before and after a single dose of a renin inhibitor.

2. Chronic effect of renin inhibition: Hemodynamic measurements will be obtained at baseline and after 12 weeks of each of the three drug treatment arms above.

The study lasts 12 weeks and plans to study 45 hypertensive adults over the next two years.

Condition or Disease	Intervention/Treatment	Phase
Insulin Sensitivity; Aortic Compliance; Diastolic Function	Drug: Aliskiren; Drug: Valsartan and Aliskiren; Drug: Amlodipine	N/A

Study Design

• Study Type: Interventional
• Actual Enrollment: 24 participants
• Allocation: Randomized
• Intervention Model: Single Group Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: Assessment of Renin Inhibition on Insulin Sensitivity, Diastolic Function and Aortic Compliance
• Study Start Date: Jun 1, 2010
• Actual Primary Completion Date: Dec 1, 2012
• Actual Study Completion Date: Dec 1, 2012

Arms and Interventions

Arm	Intervention/Treatment
Placebo Comparator: Valsartan and Aliskiren Valsartan 150 mg and Aliskiren (150 mg followed by force titration to 300 mg)	Drug: Valsartan and Aliskiren; Subject taking combination of valsartan and aliskiren.
Experimental: Aliskiren	Drug: Aliskiren; Aliskiren 150 mg daily for 10 weeks, force titrated after initial 2 weeks.
Placebo Comparator: Placebo Group Only taking Amlodipine	Drug: Amlodipine; Taking Amlodipine as prescribed by MD for management of high blood pressure.

Outcome Measures

Primary Outcome Measures

1. Change in Insulin Sensitivity by HOMA at 12 Weeks [12 weeks]

   The difference (change) in HOMA calculated as Baseline HOMA minus 12-week HOMA value

Secondary Outcome Measures

1. Aortic Compliance [12 weeks]

   Characteristic aortic imedeance, dynes x s/cm5

Other Outcome Measures

1. Pulse Wave Velocity [12 weeks]

   Measure of pulsewave velocity cm/s

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 75 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Men and women, 18-70 years old

• BMI =/< 35

• BP: BP > 145/95 on no BP medication or on 3 or less BP medications

• HOMA =>2.5

• Any race

Exclusion Criteria:

• 4 or more BP medications

• Intolerance or known prior adverse history from taking the medications amlodipine, aliskiren or valsartan

• BP >170/110 on screening exam

• Alcohol intake >12 oz per week

• Current smoking

• Recreational drug use

• Known or suspected secondary hypertension

• Known history of coronary artery disease, cerebrovascular disease or congestive heart failure

• History or known kidney disease (eGFR <50cc/min)

• Diabetes or current metformin use, or HbA1c >=6.5% on screen

• Steroid use (oral or inhaled, chronic or within the past 6 months)

• Clinically significant screening lab abnormalities (See attached "Screening Labs Acceptable Ranges")

• Evidence of ischemia or heart block on screening electrocardiogram (greater than type I-second degree heart block, left bundle branch block, or ST-T wave changes in 2 or more contiguous leads).

• Acute hospitalizations including surgery in the past 6 months

• Chronic use of non-steroidal anti-inflammatory or narcotic medications

• Women who are pregnant or nursing, or wish to become pregnant and/or who can not agree or tolerate two forms of birth control during the study period:

Acceptable birth control methods for use in this study are:

• hormonal methods, such as birth control pills, patches, injections, vaginal ring, or implants

• barrier methods (such as a condom or diaphragm) used with a spermicide (a foam, cream, or gel that kills sperm)

• intrauterine device (IUD)

• abstinence (no sex)

• Significant concomitant medical illnesses (cancer, chronic active immunological conditions, etc.)

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Brigham and Women's Hospital	Boston	Massachusetts	United States	02115

Sponsors and Collaborators

• Brigham and Women's Hospital

Investigators

• Principal Investigator: Jonathan Williams, MD, Brigham and Women's Hospital

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Jonathan S. Williams, MD, MMSc, Jonathan Williams, MD, Brigham and Women's Hospital
• ClinicalTrials.gov Identifier: NCT01252238
• Other Study ID Numbers: 2010p001286
• First Posted: Dec 2, 2010
• Last Update Posted: Feb 13, 2018
• Last Verified: Jan 1, 2018

• Additional relevant MeSH terms: Insulin Resistance; Hypersensitivity; Amlodipine; Valsartan

Study Results

Participant Flow

Recruitment Details	Recruitment occurred from 8/2009 thru 12/2011 at Brigham and Women's Hospital, Boston, MA.
Pre-assignment Detail	All subjects washed out blood pressure medication for two weeks and ran in for two weeks on amlodipine 2.5-10mg titrated to BP <160/90 every other day. All subjects consumed a very low salt calculated diet for one week followed by calculated high salt diet for 2 weeks prior to randomization

Arm/Group Title	Aliskiren	Placebo Group	Valsartan and Aliskiren
Arm/Group Description	Aliskiren : Aliskiren 150 mg daily for 10 weeks, force titrated after initial 2 weeks.	Only taking Amlodipine Amlodipine : Taking Amlodipine as prescribed by MD for management of high blood pressure.	Valsartan 150 mg and Aliskiren (150 mg followed by force titration to 300 mg) Valsartan and Aliskiren : Subject taking combination of valsartan and aliskiren.
Period Title: Overall Study
STARTED	8	8	8
COMPLETED	4	4	4
NOT COMPLETED	4	4	4

Baseline Characteristics

Arm/Group Title	Aliskiren	Placebo Group	Valsartan and Aliskiren	Total
Arm/Group Description	Aliskiren : Aliskiren 150 mg daily for 10 weeks, force titrated after initial 2 weeks.	Only taking Amlodipine Amlodipine : Taking Amlodipine as prescribed by MD for management of high blood pressure.	Valsartan 150 mg and Aliskiren (150 mg followed by force titration to 300 mg) Valsartan and Aliskiren : Subject taking combination of valsartan and aliskiren.	Total of all reporting groups
Overall Participants	8	8	8	24
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%	0 0%
Between 18 and 65 years	7 87.5%	7 87.5%	8 100%	22 91.7%
>=65 years	1 12.5%	1 12.5%	0 0%	2 8.3%
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	47 (12)	51 (6)	47 (5)	48 (7)
Sex: Female, Male (Count of Participants)
Female	4 50%	6 75%	2 25%	12 50%
Male	4 50%	2 25%	6 75%	12 50%
Region of Enrollment (participants) [Number]
United States	8 100%	8 100%	8 100%	24 100%

Outcome Measures

1. Primary Outcome

Title	Change in Insulin Sensitivity by HOMA at 12 Weeks
Description	The difference (change) in HOMA calculated as Baseline HOMA minus 12-week HOMA value
Time Frame	12 weeks

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Aliskiren	Placebo Group	Valsartan and Aliskiren
Arm/Group Description	Aliskiren : Aliskiren 150 mg daily for 10 weeks, force titrated after initial 2 weeks.	Only taking Amlodipine Amlodipine : Taking Amlodipine as prescribed by MD for management of high blood pressure.	Valsartan 150 mg and Aliskiren (150 mg followed by force titration to 300 mg) Valsartan and Aliskiren : Subject taking combination of valsartan and aliskiren.
Measure Participants	4	4	4
Mean (Standard Deviation) [HOMA Scale]	-0.7 (1.3)	-0.4 (1.4)	-0.5 (1.5)

2. Secondary Outcome

Title	Aortic Compliance
Description	Characteristic aortic imedeance, dynes x s/cm5
Time Frame	12 weeks

Outcome Measure Data

Analysis Population Description

Comparison of Baseline vs. study drug at 12 week2

Arm/Group Title	Valsartan and Aliskiren	Aliskiren	Placebo Group
Arm/Group Description	Valsartan 150 mg and Aliskiren (150 mg followed by force titration to 300 mg) Valsartan and Aliskiren: Subject taking combination of valsartan and aliskiren.	Aliskiren: Aliskiren 150 mg daily for 10 weeks, force titrated after initial 2 weeks.	Only taking Amlodipine Amlodipine: Taking Amlodipine as prescribed by MD for management of high blood pressure.
Measure Participants	4	4	4
baseline	212 (88)	241 (63)	111 (7)
12 weeks	174 (57)	127 (0.00000)	519 (499)

3. Other Pre-specified Outcome

Title	Pulse Wave Velocity
Description	Measure of pulsewave velocity cm/s
Time Frame	12 weeks

Outcome Measure Data

Analysis Population Description

Comparison of baseline vs at 12 weeks on study drug

Arm/Group Title	Valsartan and Aliskiren	Aliskiren	Placebo Group
Arm/Group Description	Valsartan 150 mg and Aliskiren (150 mg followed by force titration to 300 mg) Valsartan and Aliskiren: Subject taking combination of valsartan and aliskiren.	Aliskiren: Aliskiren 150 mg daily for 10 weeks, force titrated after initial 2 weeks.	Only taking Amlodipine Amlodipine: Taking Amlodipine as prescribed by MD for management of high blood pressure.
Measure Participants	4	4	4
baseline	991 (338)	824 (106)	1021 (5.6)
12 weeks	824 (183)	696 (0.000000)	574 (584)

Adverse Events

Arm/Group Title	Aliskiren		Placebo Group		Valsartan and Aliskiren
Arm/Group Description	Aliskiren : Aliskiren 150 mg daily for 10 weeks, force titrated after initial 2 weeks.		Only taking Amlodipine Amlodipine : Taking Amlodipine as prescribed by MD for management of high blood pressure.		Valsartan 150 mg and Aliskiren (150 mg followed by force titration to 300 mg) Valsartan and Aliskiren : Subject taking combination of valsartan and aliskiren.
All Cause Mortality
	Aliskiren		Placebo Group		Valsartan and Aliskiren
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)		/ (NaN)
Serious Adverse Events
	Aliskiren		Placebo Group		Valsartan and Aliskiren
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/8 (0%)		0/8 (0%)		0/8 (0%)
Other (Not Including Serious) Adverse Events
	Aliskiren		Placebo Group		Valsartan and Aliskiren
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/8 (0%)		0/8 (0%)		0/8 (0%)

Limitations/Caveats

No conclusions can be drawn from study due to very low sample size. The sponsor terminated the study after a separate study reported adverse events in a diabetic population who had taken both valsartan and aliskiren.

More Information

Certain Agreements

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

There is NOT 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.