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The Potential of Candesartan to Retard the Progression of Aortic Stenosis (ROCK-AS)

Primary Purpose

Aortic Valve Stenosis

Status

Unknown status

Phase

Phase 3

Locations

Finland

Study Type

Interventional

Intervention

candesartan

placebo

About this trial

This is an interventional treatment trial for Aortic Valve Stenosis focused on measuring aortic stenosis, valve, candesartan

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

120 consecutive patients with clinically significant, symptomatic aortic stenosis referred to the Helsinki University Central Hospital for consideration of valve replacement surgery.

Exclusion Criteria:

Individuals with past myocardial infarction, more than mild mitral valve disease, or previous cardiac surgery will be excluded.
Patients with heart failure who need urgent surgery or those with hypotension (systolic blood pressure below 110 mm Hg) will be excluded.
Patients already taking ACE inhibitors or AT-1R antagonists will be excluded from the study population.
Other exclusion criteria include the following:
- Complicated diabetes
- Primary cardiomyopathy
- Pregnant women, women who are breast feeding, and women of childbearing potential who are not using chemical or mechanical contraception or have a positive serum pregnancy test
- History of malignancy (unless a documented disease free period exceeding 5-years is present) with the exception of basal cell or squamous cell carcinoma of the skin. Women with a history of cervical dysplasia would be permitted to enter the study provided they had 3 consecutive clear Papanicolaou (Pap) smears
- Hypothyroidism (TSH 1.5xULN)
- History of alcohol or drug abuse within the last 5 years (this may affect compliance)
- Unexplained creatine kinase (CK 3xULN) (To protect patient safety)
- Serum creatinine >176 umol/L (2.0mg/dL)
- Participation in another investigational drug study less than 4 weeks before enrolment in the study, or according to subjects local ethics committee requirements where a larger period is stipulated (to avoid potential misinterpretation of overlapping adverse events)

Sites / Locations

Division of Cardiology, Helsinki University Central HospitalRecruiting

Arms of the Study

Arm 1

Arm 2

Arm Type

Active Comparator

Placebo Comparator

Arm Label

Arm Description

Candesartan 8 mg/d for two weeks, then 16 mg/d until valve replacement surgery (approximately 3 months)

Placebo

Outcomes

Primary Outcome Measures

The degree of inflammation in stenotic aortic valves

Secondary Outcome Measures

The degree of calcification, lipid accumulation, and fibrosis in stenotic aortic valves

Full Information

NCT ID

NCT00699452

First Posted

June 16, 2008

Last Updated

May 18, 2009

Sponsor

University of Helsinki

Collaborators

AstraZeneca

1. Study Identification

Unique Protocol Identification Number

NCT00699452

Brief Title

The Potential of Candesartan to Retard the Progression of Aortic Stenosis

Acronym

ROCK-AS

Official Title

The Potential of Candesartan to Retard the Progression of Aortic Stenosis Influences of Medical Therapy to the Atheroinflammatory Process in Stenotic Aortic Valves

Study Type

Interventional

2. Study Status

Record Verification Date

May 2009

Overall Recruitment Status

Unknown status

Study Start Date

May 2009 (undefined)

Primary Completion Date

December 2012 (Anticipated)

Study Completion Date

December 2014 (Anticipated)

3. Sponsor/Collaborators

Name of the Sponsor

University of Helsinki

Collaborators

AstraZeneca

4. Oversight

Data Monitoring Committee

Yes

5. Study Description

Brief Summary

The present study defines a blinded, randomized, placebo-controlled, prospective study, the aim of which is to determine the influence of effective treatment with Type 1 angiotensin II (Ang II) receptor (AT-1R) antagonist, using candesartan (target dose 16 mg) on stenotic aortic valves. The investigators will specifically quantify whether candesartan attenuates the key pathogenic mechanisms of aortic valve stenosis, namely inflammation, fibrosis, elastin degradation, calcification, and neovascularization.

Detailed Description

We will include in the study 120 consecutive patients with clinically significant, symptomatic aortic stenosis referred to the Helsinki University Central Hospital for consideration of valve replacement surgery. Patients who can be put on the hospital's normal waiting list for elective angiography (i.e who do not need urgent surgery) and who give their informed consent, will be randomized into two groups to start therapy with candesartan (8 mg/d for 2 weeks, and then 16 mg/d until surgery) or placebo. On average, the overall duration of the drug intervention will be 3 months, i.e., the average time in our institution from referral to surgery. In addition, patients (n=50) undergoing aortic valve replacement surgery due to aortic regurgitation caused by dilation of the aortic root will be included. This population consists of both patients with early sclerotic, i.e., pre-stenotic, changes in their aortic valves (n=30) and of patients without any sclerotic or stenotic changes in their aortic valves (n=20). The group with sclerotic changes in their aortic valves (n=30) will be divided into two groups to receive candesartan (8 mg/d 2 wk, and then 16 mg/d until surgery) (n=15) or placebo (n=15). The removed aortic valves will be examined utilizing real-time PCR, autoradiography, fluorometry, immunohistochemistry, double immunofluorescence, confocal microscopy, and enzyme immunoassays. With these techniques, several markers of inflammation, calcification, fibrosis, and the amount of lipid accumulation and oxidation of LDL in the valves will be examined.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Aortic Valve Stenosis

Keywords

aortic stenosis, valve, candesartan

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 3

Interventional Study Model

Parallel Assignment

Masking

ParticipantCare ProviderInvestigator

Allocation

Randomized

Enrollment

120 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title

Arm Type

Active Comparator

Arm Description

Candesartan 8 mg/d for two weeks, then 16 mg/d until valve replacement surgery (approximately 3 months)

Arm Title

Arm Type

Placebo Comparator

Arm Description

Placebo

Intervention Type

Drug

Intervention Name(s)

candesartan

Other Intervention Name(s)

Atacand

Intervention Description

Candesartan 8 mg/d for two weeks, then 16 mg/d until valve replacement surgery (approximately 3 months)

Intervention Type

Drug

Intervention Name(s)

placebo

Intervention Description

placebo

Primary Outcome Measure Information:

Title

The degree of inflammation in stenotic aortic valves

Time Frame

3-5 months

Secondary Outcome Measure Information:

Title

The degree of calcification, lipid accumulation, and fibrosis in stenotic aortic valves

Time Frame

3-5 months

10. Eligibility

Sex

All

Minimum Age & Unit of Time

18 Years

Accepts Healthy Volunteers

Eligibility Criteria

Inclusion Criteria: 120 consecutive patients with clinically significant, symptomatic aortic stenosis referred to the Helsinki University Central Hospital for consideration of valve replacement surgery. Exclusion Criteria: Individuals with past myocardial infarction, more than mild mitral valve disease, or previous cardiac surgery will be excluded. Patients with heart failure who need urgent surgery or those with hypotension (systolic blood pressure below 110 mm Hg) will be excluded. Patients already taking ACE inhibitors or AT-1R antagonists will be excluded from the study population. Other exclusion criteria include the following: Complicated diabetes Primary cardiomyopathy Pregnant women, women who are breast feeding, and women of childbearing potential who are not using chemical or mechanical contraception or have a positive serum pregnancy test History of malignancy (unless a documented disease free period exceeding 5-years is present) with the exception of basal cell or squamous cell carcinoma of the skin. Women with a history of cervical dysplasia would be permitted to enter the study provided they had 3 consecutive clear Papanicolaou (Pap) smears Hypothyroidism (TSH 1.5xULN) History of alcohol or drug abuse within the last 5 years (this may affect compliance) Unexplained creatine kinase (CK 3xULN) (To protect patient safety) Serum creatinine >176 umol/L (2.0mg/dL) Participation in another investigational drug study less than 4 weeks before enrolment in the study, or according to subjects local ethics committee requirements where a larger period is stipulated (to avoid potential misinterpretation of overlapping adverse events)

Central Contact Person:

First Name & Middle Initial & Last Name or Official Title & Degree

Markku Kupari, MD, PhD

Phone

358-9-4717-2441

markku.kupari@hus.fi

First Name & Middle Initial & Last Name or Official Title & Degree

Satu Helske, MD, PhD

Phone

358-9-681-411

satu.helske@wri.fi

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Markku Kupari, MD, PhD

Organizational Affiliation

Division of Cardiology, Helsinki University Central Hospital

Official's Role

Principal Investigator

Facility Information:

Facility Name

Division of Cardiology, Helsinki University Central Hospital

City

Helsinki

ZIP/Postal Code

00029

Country

Finland

Individual Site Status

Recruiting

Facility Contact:

First Name & Middle Initial & Last Name & Degree

Markku Kupari, MD, PhD

Phone

358-9-4717-2441

markku.kupari@hus.fi

First Name & Middle Initial & Last Name & Degree

Satu Helske, MD, PhD

Phone

358-9-681-411

satu.helske@wri.fi

First Name & Middle Initial & Last Name & Degree

Markku Kupari, MD, PhD

12. IPD Sharing Statement

Citations:

PubMed Identifier

25469804

Citation

Helske-Suihko S, Laine M, Lommi J, Kaartinen M, Werkkala K, Kovanen PT, Kupari M. Is blockade of the Renin-Angiotensin system able to reverse the structural and functional remodeling of the left ventricle in severe aortic stenosis? J Cardiovasc Pharmacol. 2015 Mar;65(3):233-40. doi: 10.1097/FJC.0000000000000182.

Results Reference

derived

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The Potential of Candesartan to Retard the Progression of Aortic Stenosis

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