Simvastatin as a Treatment for Pulmonary Hypertension

The purpose of the study is to investigate the safety and efficacy of adding simvastatin to the current conventional treatment regimen for the management of pulmonary hypertension.

Study Overview

• Status: Completed
• Conditions: Pulmonary Hypertension
• Intervention / Treatment: Drug: Placebo; Drug: Simvastatin

Detailed Description

Pulmonary arterial hypertension (PAH) is a disease that is characterised by progressive narrowing of the blood vessels of the lungs. This results in a pressure load on the heart and heart failure.

The narrowing is in part due to constriction but mostly due to structural changes in affected vessels. The structural changes affect all cell components of the vessel wall (the endothelial lining, the muscle layer and fibrous tissue) and can lead to local clot formation. In addition there is evidence of inflammation of the vessels and what is known as oxidative stress. The disease may occur with no obvious cause, when it is known as idiopathic, but it can also be associated with a variety of other diseases, including congenital heart disease, collagen vascular disease and HIV infection.

Current approaches to the treatment of pulmonary hypertension are unsatisfactory as they do not prevent disease progression and do not directly or adequately address many of the processes detailed above. Alternative or additional treatments are therefore required and an attrative approach is to use a statin (a 3-hydroxy-3-methylglutaryl-coenzymeA, or HMG-CoA, reductase inhibitor). Statins are widely used for their ability to lower blood cholesterol but increasing evidence indicates that these drugs also have direct effects on cell components of the vessel wall - including inhibiting inflammation, clot formation and oxidative stress - that might be beneficial in pulmonary hypertension.

• Study Type: Interventional
• Enrollment (Actual): 42
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• Germany
  • Gießen, Germany
    • Department of Internal Medicine II, Klinikstrasse 36 D-35392
• United Kingdom
  • London, United Kingdom, SW3 6NP
    • Royal Brompton Hospital, Sydney Street
  • London, United Kingdom, W12 0NN
    • Hammersmith Hospital, Du Cane Road

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Patients with idiopathic PAH or PAH related to collagen vascular disease
• Age 18 years or over
• Receiving conventional therapy with diuretics, digoxin, warfarin, sildenafil and bosentan. Stable for 1 month
• 6 minute walk distance between 150m and 450m
• Modified NYHA functional class II or III

Exclusion Criteria:

• PAH from a cause other than permitted by entry criteria
• Change in PAH treatment in past 4 weeks
• Patients requiring prostanoid therapy
• Patients already taking a statin
• Clinically significant disturbance of liver function - AST or ALT >3xULM; bilirubin >1.5xULM
• Contraindication for a magnetic resonance scan

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: Arm 1: Control; Placebo tablet once daily	Drug: Placebo; Placebo tablet once daily.
Experimental: Arm 2: Experimental; Simvastatin 40mg od for 1 month, then uptitrated to 80mg od for 11 months.	Drug: Simvastatin; Simvastatin 40mg od for 1 month, then 80mg od for 11 months; Other Names: Zocor

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in Right Ventricular Mass From Baseline	As measured by cardiac magnetic resonance (the study is powered to detect an 8.5g difference in RV mass between the two treatments, based on reproducibility measurements of RV mass in healthy volunteers and patients)	6 months post study treatment

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in 6-minute Walk Distance	Change in distance achieved in 6 minute walk test from baseline	6 months
Change in LV Mass	Change in LV mass from baseline based on cardiac MRI	6 months
Circulating Levels of BNP	Change in NT-proBNP levels compared to baseline	6 months
Change in Quality of Life Score	Change in quality of life score from baseline as measured by Cambridge Pulmonary Hypertension Outcome Review (CAMPHOR) scored from 1-25, with higher scores indicating worse quality of life, the investigator reported the score change.	6 months

Collaborators and Investigators

• Sponsor: Imperial College London
• Collaborators: Medical Research Council
• Investigators: Principal Investigator: Martin Wilkins, MD FRCP, Imperial College London

Publications and helpful links

General Publications

• Wilkins MR, Ali O, Bradlow W, Wharton J, Taegtmeyer A, Rhodes CJ, Ghofrani HA, Howard L, Nihoyannopoulos P, Mohiaddin RH, Gibbs JS; Simvastatin Pulmonary Hypertension Trial (SiPHT) Study Group. Simvastatin as a treatment for pulmonary hypertension trial. Am J Respir Crit Care Med. 2010 May 15;181(10):1106-13. doi: 10.1164/rccm.2009111-699oc.

Study record dates

Study Major Dates

• Study Start (Actual): October 1, 2005
• Primary Completion (Actual): October 1, 2008
• Study Completion (Actual): May 1, 2009

Study Registration Dates

• First Submitted: September 12, 2005
• First Submitted That Met QC Criteria: September 12, 2005
• First Posted (Estimate): September 16, 2005

Study Record Updates

• Last Update Posted (Actual): August 21, 2019
• Last Update Submitted That Met QC Criteria: August 20, 2019
• Last Verified: August 1, 2019

More Information

Terms related to this study

• Keywords: Pulmonary hypertension; Statins; Simvastatin
• Additional Relevant MeSH Terms: Cardiovascular Diseases; Vascular Diseases; Respiratory Tract Diseases; Lung Diseases; Hypertension; Hypertension, Pulmonary; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antimetabolites; Anticholesteremic Agents; Hypolipidemic Agents; Lipid Regulating Agents; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Simvastatin
• Other Study ID Numbers: WILK10554

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO