ALPINE: Aliskiren Effect on Aortic Plaque Progression

• Sponsor: Ohio State University (Other)
• Overall Status: Terminated
• CT.gov ID: NCT01417104
• Collaborator: Novartis (Industry)
• Enrollment: 71
• Location: 1
• Arms: 2
• Duration (Months): 27
• Patients Per Site Per Month: 2.6

Study Details

Study Description

Brief Summary

This study is being done to assess the effectiveness of short term (~9 months) Aliskiren/Placebo therapy to slow down the progression of atherosclerotic disease in thoracic and abdominal aorta. This will be checked by comparing before and after therapy magnetic resonance imaging (MRI) pictures of the aortic wall. Aliskiren is an FDA approved drug for hypertension but in this study is used for a new indication. Recent studies with animals have shown that Aliskiren therapy reduces the atherosclerotic plaque. Therefore, in this study, the investigators would like to evaluate whether the investigational drug Aliskiren, which is not FDA approved for this indication has the same beneficial effects in people with atherosclerotic disease.

Condition or Disease	Intervention/Treatment	Phase
Atherosclerosis	Drug: Aliskiren; Drug: Placebo	Phase 2/Phase 3

Detailed Description

Treatments and Clinic Visits:

The 36-week double-blind, randomized treatment phase of the trial is preceded by 2-week single-blind placebo period to assess eligibility into the active treatment period, compliance, and to confirm the baseline blood pressure values of the enrolled subjects. If at the end of the single-blind phase, inclusion criteria will not be met, the participants will not be allowed to continue on to the trial. If they are eligible they will undergo baseline MRI studies after being randomized to either placebo or Aliskiren 150 mg, with an escalation to 300 mg at 2 weeks into treatment. This dose will be maintained for the duration of the trial. After randomization and dose escalation visits (at 2 weeks), patients will return for scheduled clinic visits at weeks 12 and 36. Assessment of routine safety measures including serum creatinine and potassium will be performed at pre-designated visits (randomization, drug escalation and end-of trial). At each study visit, after having the patient in a sitting position for 5 minutes, SBP/diastolic blood pressure will be measured 3 times in accordance with the AHA Committee Report on blood pressure determination. The patient will be then asked to stand for 2 minutes, and a single blood pressure measurement will be measured in the standing position. Evidence of left ventricular hypertrophy (LVH) will be determined using the Romhilt-Estes scoring system at baseline. Specialized measurements of plasma including insulin, glucose measures, adipokines (leptin and adiponectin) and high- sensitivity C-reactive protein (hsCRP) will be performed at randomization and 12 weeks into the trial. Central aortic blood pressure assessment will be performed at randomization and end of trial/exit visits (SphygmoCor CP, AtCor Medical, Itaska, Illinois, USA). Plasma direct renin measurements will be obtained at baseline and 12 weeks in part to assess compliance of patients with their therapy (Diasource, Belgium).

Study Design

• Study Type: Interventional
• Actual Enrollment: 71 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: Aliskiren Effect on Plaque Progression In Established Atherosclerosis Using High Resolution 3D MRI (ALPINE): A Double Blind Placebo Controlled Trial
• Study Start Date: Oct 1, 2009
• Actual Primary Completion Date: Dec 1, 2011
• Actual Study Completion Date: Jan 1, 2012

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: Aliskiren Aliskiren will be administered for 2 weeks at 150mg/day oral pill, followed by 34 weeks oral therapy with 300mg/day	Drug: Aliskiren; 150 mg/300mg; Other Names: Tekturna
Placebo Comparator: Placebo Placebo (sugar pill) built to mimic both the 150mg Aliskiren tablet ( administered for the first 2 weeks) and the 300mg Aliskiren tablet ( administered for the rest of treatment period)	Drug: Placebo; 150mg/300mg; Other Names: Sugar Pill

Outcome Measures

Primary Outcome Measures

1. Change in Normalized Total Aortic Wall Volume (TWV) Between the Trial Arms at the End of the Treatment [Baseline and end of treatment ( 17 to 36 weeks)]

   All patients underwent imaging using a 3T, MRI system. The MRI sequence method used for wall depiction was a 3D, fat suppressed, dark blood, turbo spin echo sequence with variable flip angles (SPACE). Following co-registration of pre and post treatment MR images, and generation of MPR sections, images were magnified, contrast adjusted and patient/exam identifier information was removed and replaced by pre-assigned code to blind images for measurements. An experienced observer performed manual measurements of lumen and lumen plus wall areas by delineating the inner border and the outer border of the vessel wall in each cross-section image of the aorta. Using an approach similar to intravascular atheroma volume calculations, normalized total aortic wall volume (TWV) for thoracic region, abdominal region and total aorta for each patient and each exam was generated.

Secondary Outcome Measures

1. Change in the Percentage Wall Volume (PWV) Between Baseline and End of Treatment [Baseline and end of treatment ( 17 to 36 weeks)]

   Using an approach similar to intravascular atheroma volume calculations, percentage wall volume (PWV) for thoracic region, abdominal region and total aorta for each patient and each exam was generated. and a difference between baseline and end of treatment was calculated.

Other Outcome Measures

1. Change From Baseline in Resting Diastolic Blood Pressure [baseline to end of treatment ( up to 36 weeks)]

   Difference between end of treatment and baseline in resting diastolic blood pressure

Eligibility Criteria

Criteria

• Ages Eligible for Study: 45 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria: Patients, both males and females, were eligible if they were ≥ 45 years of age, with previously documented cardiovascular disease, defined as at least one of the following: myocardial infarction (MI), cerebrovascular accident (CVA), coronary bypass surgery and/or percutaneous intervention, peripheral arterial disease (PAD), defined as ankle brachial index (ABI) <0.9 and/or prior peripheral intervention/surgery. Subjects on angiotensin-converting enzyme inhibitor (ACEI) or angiotensin receptor blockers (ARB) therapy were eligible to participate, provided no dose adjustments were made during the course of the study.

Exclusion Criteria: Contraindications to the MRI exam (pacemakers, metallic implants, severe claustrophobia); diagnosis of Type II Diabetes or use of hypoglycemic drugs; uncontrolled hypertension (>145/90 mm Hg); low density lipoprotein (LDL) of ≥ 130mg/dL; renal insufficiency defined as glomerular filtration rate (GFR) ≤ 40 ml/minute (derived by the Modified Diet in Renal Disease (MDRD) equation); initiation of new therapy with statins, ACEI/ARBs, anti-oxidants, calcium channel blockers, diuretics, β blockers; transient ischemic cerebral attack during the prior 6 months; history of allergy to renin inhibitors; unstable cardiac syndromes; symptomatic arrhythmias; history of malignancy including leukemia and lymphoma (but not basal cell skin cancer, cured squamous cell cancer and localized prostate cancer) and history of allergy to renin inhibitors.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Ohio State University	Columbus	Ohio	United States	43210

Sponsors and Collaborators

• Ohio State University
• Novartis

Investigators

• Principal Investigator: Sanjay Rajagopalan, MD, Ohio State University

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Ohio State University
• ClinicalTrials.gov Identifier: NCT01417104
• Other Study ID Numbers: CSPP100AUS33T; NCT01123629
• First Posted: Aug 16, 2011
• Last Update Posted: May 11, 2017
• Last Verified: May 1, 2017

• Keywords provided by Ohio State University: plaque; magnetic resonance imaging (MRI); high blood pressure; MI; heart attack; CVA; stroke; PAD
• Additional relevant MeSH terms: Atherosclerosis

Study Results

Participant Flow

Recruitment Details	Participants recruited from The Ohio State Medical Center and Columbus surrounding area between April 2009 to December 2011.
Pre-assignment Detail	187 participants screened; 116 did not meet inclusion criteria or meet exclusion criteria; 71 randomized.

Arm/Group Title	Aliskiren	Placebo
Arm/Group Description	Aliskiren will be administered for 2 weeks at 150mg/day oral pill, followed by 34 weeks oral therapy with 300mg/day	Placebo (sugar pill) built to mimic both the 150mg Aliskiren tablet ( administered for the first 2 weeks) and the 300mg Aliskiren tablet ( administered for the rest of treatment period)
Period Title: Overall Study
STARTED	34	37
COMPLETED	28	35
NOT COMPLETED	6	2

Baseline Characteristics

Arm/Group Title	Aliskiren	Placebo	Total
Arm/Group Description	Aliskiren will be administered for 2 weeks at 150mg/day oral pill, followed by 34 weeks oral therapy with 300mg/day	Placebo (sugar pill) built to mimic both the 150mg Aliskiren tablet ( administered for the first 2 weeks) and the 300mg Aliskiren tablet ( administered for the rest of treatment period)	Total of all reporting groups
Overall Participants	34	37	71
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%
Between 18 and 65 years	17 50%	13 35.1%	30 42.3%
>=65 years	17 50%	24 64.9%	41 57.7%
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	63.9 (11.5)	64.5 (8.9)	64.18 (10.17)
Sex: Female, Male (Count of Participants)
Female	9 26.5%	3 8.1%	12 16.9%
Male	25 73.5%	34 91.9%	59 83.1%
Region of Enrollment (participants) [Number]
United States	34 100%	37 100%	71 100%

Outcome Measures

1. Primary Outcome

Title	Change in Normalized Total Aortic Wall Volume (TWV) Between the Trial Arms at the End of the Treatment
Description	All patients underwent imaging using a 3T, MRI system. The MRI sequence method used for wall depiction was a 3D, fat suppressed, dark blood, turbo spin echo sequence with variable flip angles (SPACE). Following co-registration of pre and post treatment MR images, and generation of MPR sections, images were magnified, contrast adjusted and patient/exam identifier information was removed and replaced by pre-assigned code to blind images for measurements. An experienced observer performed manual measurements of lumen and lumen plus wall areas by delineating the inner border and the outer border of the vessel wall in each cross-section image of the aorta. Using an approach similar to intravascular atheroma volume calculations, normalized total aortic wall volume (TWV) for thoracic region, abdominal region and total aorta for each patient and each exam was generated.
Time Frame	Baseline and end of treatment ( 17 to 36 weeks)

Outcome Measure Data

Analysis Population Description

3 MRI data sets were not analyzable ( low quality images), and 23 post-treatment MRI not obtained ( <17 weeks on drug when trial terminated owing to ALTITUDE results)

Arm/Group Title	Aliskiren	Placebo
Arm/Group Description	Aliskiren was administered for 2 weeks at 150mg/day oral pill, followed by 34 weeks oral therapy with 300mg/day	Placebo (sugar pill) built to mimic both the 150mg Aliskiren tablet ( administered for the first 2 weeks) and the 300mg Aliskiren tablet ( administered for the rest of treatment period)
Measure Participants	18	19
Mean (Standard Deviation) [mm3]	5.31 (6.57)	0.15 (4.39)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Aliskiren, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.031
	Comments
	Method	t-test, 2 sided
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	5.16
	Confidence Interval	(2-Sided) 95%; 0.85 to 9.47
	Parameter Dispersion	Type: Value:
	Estimation Comments

2. Secondary Outcome

Title	Change in the Percentage Wall Volume (PWV) Between Baseline and End of Treatment
Description	Using an approach similar to intravascular atheroma volume calculations, percentage wall volume (PWV) for thoracic region, abdominal region and total aorta for each patient and each exam was generated. and a difference between baseline and end of treatment was calculated.
Time Frame	Baseline and end of treatment ( 17 to 36 weeks)

Outcome Measure Data

Analysis Population Description

3 MRI not analyzable, 23 final MRI not obtained due to trial termination

Arm/Group Title	Aliskiren	Placebo
Arm/Group Description	Aliskiren was administered for 2 weeks at 150mg/day oral pill, followed by 34 weeks oral therapy with 300mg/day	Placebo (sugar pill) built to mimic both the 150mg Aliskiren tablet ( administered for the first 2 weeks) and the 300mg Aliskiren tablet ( administered for the rest of treatment period)
Measure Participants	18	19
Mean (Standard Deviation) [Percentage of the Outer Wall Volume]	3.37 (2.96)	0.97 (2.02)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Aliskiren, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.041
	Comments
	Method	t-test, 2 sided
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	2.40
	Confidence Interval	(2-Sided) 95%; 0.44 to 4.36
	Parameter Dispersion	Type: Value:
	Estimation Comments

3. Other Pre-specified Outcome

Title	Change From Baseline in Resting Diastolic Blood Pressure
Description	Difference between end of treatment and baseline in resting diastolic blood pressure
Time Frame	baseline to end of treatment ( up to 36 weeks)

Outcome Measure Data

Analysis Population Description

Intent to treat analysis including only participants who had at least one post-baseline assesment

Arm/Group Title	Aliskiren	Placebo
Arm/Group Description	Aliskiren was administered for 2 weeks at 150mg/day oral pill, followed by 34 weeks oral therapy with 300mg/day	Placebo (sugar pill) built to mimic both the 150mg Aliskiren tablet ( administered for the first 2 weeks) and the 300mg Aliskiren tablet ( administered for the rest of treatment period)
Measure Participants	28	35
Mean (95% Confidence Interval) [mm Hg]	-3.88	-2.32

Adverse Events

Time Frame	up to 36 weeks
Arm/Group Title	Aliskiren		Placebo
Arm/Group Description	Aliskiren was administered for 2 weeks at 150mg/day oral pill, followed by 34 weeks oral therapy with 300mg/day		Placebo (sugar pill) built to mimic both the 150mg Aliskiren tablet ( administered for the first 2 weeks) and the 300mg Aliskiren tablet ( administered for the rest of treatment period)
All Cause Mortality
	Aliskiren		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Aliskiren		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/34 (0%)		0/37 (0%)
Other (Not Including Serious) Adverse Events
	Aliskiren		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	1/34 (2.9%)		0/37 (0%)
Metabolism and nutrition disorders
Hyperkalemia	1/34 (2.9%)	1	0/37 (0%)	0

Limitations/Caveats

[Not Specified]

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.