Pulmonary Hypertension
Conditions
Keywords
Pulmonary hypertension, Simvastatin, Statins
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.
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.
Interventions
DRUGSimvastatin
Simvastatin 40mg od for 1 month, then 80mg od for 11 months
DRUGPlacebo
Placebo tablet once daily.
Sponsors
Medical Research Council
Imperial College London
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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
| Measure | Time frame | Description |
|---|---|---|
| Change in 6-minute Walk Distance | 6 months | Change in distance achieved in 6 minute walk test from baseline |
| Change in LV Mass | 6 months | Change in LV mass from baseline based on cardiac MRI |
| Circulating Levels of BNP | 6 months | Change in NT-proBNP levels compared to baseline |
| 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. |
Countries
Germany, United Kingdom
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Arm 1: Control Placebo tablet once daily
Placebo: Placebo tablet once daily. | 23 |
| Arm 2: Experimental 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 | 19 |
| Total | 42 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 3 | 3 |
| Overall Study | Withdrawal by Subject | 2 | 0 |
Baseline characteristics
| Characteristic | Arm 2: Experimental | Total | Arm 1: Control |
|---|---|---|---|
| Age, Continuous | 43.2 years | 46.2 years | 49.1 years |
| Race/Ethnicity, Customized Black | 1 participants | 1 participants | 0 participants |
| Race/Ethnicity, Customized Other | 7 participants | 9 participants | 2 participants |
| Race/Ethnicity, Customized White | 11 participants | 32 participants | 21 participants |
| Sex: Female, Male Female | 17 Participants | 32 Participants | 15 Participants |
| Sex: Female, Male Male | 2 Participants | 10 Participants | 8 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 0 / 23 | 2 / 19 |
| serious Total, serious adverse events | 1 / 23 | 0 / 19 |
Outcome results
Primary
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)
Time frame: 6 months post study treatment
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Arm 1: Control | Change in Right Ventricular Mass From Baseline | 3.9 grams | Standard Deviation 13.9 |
| Arm 2: Experimental | Change in Right Ventricular Mass From Baseline | -5.2 grams | Standard Deviation 11.3 |
p-value: 0.028ANOVA
Secondary
Change in 6-minute Walk Distance
Change in distance achieved in 6 minute walk test from baseline
Time frame: 6 months
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Arm 1: Control | Change in 6-minute Walk Distance | 1 metres | Standard Deviation 57 |
| Arm 2: Experimental | Change in 6-minute Walk Distance | 3.1 metres | Standard Deviation 34.5 |
Comparison: 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.p-value: 0.86ANOVA
Secondary
Change in LV Mass
Change in LV mass from baseline based on cardiac MRI
Time frame: 6 months
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Arm 1: Control | Change in LV Mass | -1.3 grams | Standard Deviation 10.9 |
| Arm 2: Experimental | Change in LV Mass | 1.7 grams | Standard Deviation 12.3 |
Comparison: 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.p-value: 0.4ANOVA
Secondary
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.
Time frame: 6 months
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Arm 1: Control | Change in Quality of Life Score | 0 change of score | Standard Deviation 4.7 |
| Arm 2: Experimental | Change in Quality of Life Score | -1.6 change of score | Standard Deviation 4 |
p-value: 0.26ANOVA
Secondary
Circulating Levels of BNP
Change in NT-proBNP levels compared to baseline
Time frame: 6 months
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Arm 1: Control | Circulating Levels of BNP | 49 fmol/ml | Standard Deviation 224 |
| Arm 2: Experimental | Circulating Levels of BNP | -75 fmol/ml | Standard Deviation 167 |
p-value: 0.041ANOVA