Simvastatin as a Treatment for Pulmonary Hypertension

• Sponsor: Imperial College London (Other)
• Overall Status: Completed
• CT.gov ID: NCT00180713
• Collaborator: Medical Research Council (Other)
• Enrollment: 42
• Locations: 3
• Arms: 2
• Actual Duration (Months): 43
• Patients Per Site: 14
• Patients Per Site Per Month: 0.3

Study Details

Study Description

Brief Summary

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.

Condition or Disease	Intervention/Treatment	Phase
Pulmonary Hypertension	Drug: Simvastatin; Drug: Placebo	Phase 1/Phase 2

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 Design

• Study Type: Interventional
• Actual Enrollment: 42 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: Simvastatin as a Treatment for Pulmonary Hypertension
• Actual Study Start Date: Oct 1, 2005
• Actual Primary Completion Date: Oct 1, 2008
• Actual Study Completion Date: May 1, 2009

Arms and Interventions

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

Outcome Measures

Primary Outcome Measures

1. Change in Right Ventricular Mass From Baseline [6 months post study treatment]

   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)

Secondary Outcome Measures

1. Change in 6-minute Walk Distance [6 months]

   Change in distance achieved in 6 minute walk test from baseline

2. Change in LV Mass [6 months]

   Change in LV mass from baseline based on cardiac MRI

3. Circulating Levels of BNP [6 months]

   Change in NT-proBNP levels compared to baseline

4. Change in Quality of Life Score [6 months]

   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.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Department of Internal Medicine II, Klinikstrasse 36 D-35392	Gießen		Germany
2	Royal Brompton Hospital, Sydney Street	London		United Kingdom	SW3 6NP
3	Hammersmith Hospital, Du Cane Road	London		United Kingdom	W12 0NN

Sponsors and Collaborators

• Imperial College London
• Medical Research Council

Investigators

• Principal Investigator: Martin Wilkins, MD FRCP, Imperial College London

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Imperial College London
• ClinicalTrials.gov Identifier: NCT00180713
• Other Study ID Numbers: WILK10554
• First Posted: Sep 16, 2005
• Last Update Posted: Aug 21, 2019
• Last Verified: Aug 1, 2019

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• Keywords provided by Imperial College London: Pulmonary hypertension; Simvastatin; Statins
• Additional relevant MeSH terms: Hypertension, Pulmonary; Hypertension; Simvastatin

Study Results

Participant Flow

Arm/Group Title	Arm 1: Control	Arm 2: Experimental
Arm/Group Description	Placebo tablet once daily Placebo: Placebo tablet once daily.	Simvastatin 40mg od for 1 month, then uptitrated to 80mg od for 11 months. Simvastatin: Simvastatin 40mg od for 1 month, then 80mg od for 11 months
Period Title: Overall Study
STARTED	23	19
COMPLETED	18	16
NOT COMPLETED	5	3

Baseline Characteristics

Arm/Group Title	Arm 1: Control	Arm 2: Experimental	Total
Arm/Group Description	Placebo tablet once daily Placebo: Placebo tablet once daily.	Simvastatin 40mg od for 1 month, then uptitrated to 80mg od for 11 months. Simvastatin: Simvastatin 40mg od for 1 month, then 80mg od for 11 months	Total of all reporting groups
Overall Participants	23	19	42
Age (years) [Mean (Full Range) ]
Mean (Full Range) [years]	49.1	43.2	46.2
Sex: Female, Male (Count of Participants)
Female	15 65.2%	17 89.5%	32 76.2%
Male	8 34.8%	2 10.5%	10 23.8%
Race/Ethnicity, Customized (participants) [Number]
White	21 91.3%	11 57.9%	32 76.2%
Black	0 0%	1 5.3%	1 2.4%
Other	2 8.7%	7 36.8%	9 21.4%

Outcome Measures

1. Primary Outcome

Title	Change in Right Ventricular Mass From Baseline
Description	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)
Time Frame	6 months post study treatment

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Arm 1: Control	Arm 2: Experimental
Arm/Group Description	Placebo tablet once daily Placebo: Placebo tablet once daily.	Simvastatin 40mg od for 1 month, then uptitrated to 80mg od for 11 months. Simvastatin: Simvastatin 40mg od for 1 month, then 80mg od for 11 months
Measure Participants	23	19
Mean (Standard Deviation) [grams]	3.9 (13.9)	-5.2 (11.3)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Arm 1: Control, Arm 2: Experimental
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.028
	Comments
	Method	ANOVA
	Comments

2. Secondary Outcome

Title	Change in 6-minute Walk Distance
Description	Change in distance achieved in 6 minute walk test from baseline
Time Frame	6 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Arm 1: Control	Arm 2: Experimental
Arm/Group Description	Placebo tablet once daily Placebo: Placebo tablet once daily.	Simvastatin 40mg od for 1 month, then uptitrated to 80mg od for 11 months. Simvastatin: Simvastatin 40mg od for 1 month, then 80mg od for 11 months
Measure Participants	23	19
Mean (Standard Deviation) [metres]	1 (57)	3.1 (34.5)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Arm 1: Control, Arm 2: Experimental
	Comments	Analysis was performed by intention to treat at 6 months and per protocol at 12 months. Missing variables were replaced with medians or means (for variables missing at baseline) or with expected variables calculated on the percentage change between baseline and 24 weeks observed for the group (placebo or statin) as a whole (a technique called imputation). Missing variables accounted for less than 5% of the data and there were no missing CMR data at baseline.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.86
	Comments
	Method	ANOVA
	Comments

3. Secondary Outcome

Title	Change in LV Mass
Description	Change in LV mass from baseline based on cardiac MRI
Time Frame	6 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Arm 1: Control	Arm 2: Experimental
Arm/Group Description	Placebo tablet once daily Placebo: Placebo tablet once daily.	Simvastatin 40mg od for 1 month, then uptitrated to 80mg od for 11 months. Simvastatin: Simvastatin 40mg od for 1 month, then 80mg od for 11 months
Measure Participants	23	19
Mean (Standard Deviation) [grams]	-1.3 (10.9)	1.7 (12.3)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Arm 1: Control, Arm 2: Experimental
	Comments	Analysis was performed by intention to treat at 6 months and per protocol at 12 months. Missing variables were replaced with medians or means (for variables missing at baseline) or with expected variables calculated on the percentage change between baseline and 24 weeks observed for the group (placebo or statin) as a whole (a technique called imputation). Missing variables accounted for less than 5% of the data and there were no missing CMR data at baseline.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.4
	Comments
	Method	ANOVA
	Comments

4. Secondary Outcome

Title	Circulating Levels of BNP
Description	Change in NT-proBNP levels compared to baseline
Time Frame	6 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Arm 1: Control	Arm 2: Experimental
Arm/Group Description	Placebo tablet once daily Placebo: Placebo tablet once daily.	Simvastatin 40mg od for 1 month, then uptitrated to 80mg od for 11 months. Simvastatin: Simvastatin 40mg od for 1 month, then 80mg od for 11 months
Measure Participants	23	19
Mean (Standard Deviation) [fmol/ml]	49 (224)	-75 (167)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Arm 1: Control, Arm 2: Experimental
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.041
	Comments
	Method	ANOVA
	Comments

5. Secondary Outcome

Title	Change in Quality of Life Score
Description	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.
Time Frame	6 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Arm 1: Control	Arm 2: Experimental
Arm/Group Description	Placebo tablet once daily Placebo: Placebo tablet once daily.	Simvastatin 40mg od for 1 month, then uptitrated to 80mg od for 11 months. Simvastatin: Simvastatin 40mg od for 1 month, then 80mg od for 11 months
Measure Participants	23	19
Mean (Standard Deviation) [change of score]	0 (4.7)	-1.6 (4)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Arm 1: Control, Arm 2: Experimental
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.26
	Comments
	Method	ANOVA
	Comments

Adverse Events

Time Frame	Adverse events were collected from date of consent until the final study visit after a year.
Arm/Group Title	Arm 1: Control		Arm 2: Experimental
Arm/Group Description	Placebo tablet once daily Placebo: Placebo tablet once daily.		Simvastatin 40mg od for 1 month, then uptitrated to 80mg od for 11 months. Simvastatin: Simvastatin 40mg od for 1 month, then 80mg od for 11 months
All Cause Mortality
	Arm 1: Control		Arm 2: Experimental
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Arm 1: Control		Arm 2: Experimental
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	1/23 (4.3%)		0/19 (0%)
Nervous system disorders
Stroke	1/23 (4.3%)	1	0/19 (0%)	0
Other (Not Including Serious) Adverse Events
	Arm 1: Control		Arm 2: Experimental
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/23 (0%)		2/19 (10.5%)
Investigations
Elevated Creatinine Kinase	0/23 (0%)	0	2/19 (10.5%)	2

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

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

Standard terms of model non-commercial agreement for UK clinical research apply.