Clinical trial NCT00384865: A Study of Aspirin and Simvastatin in Pulmonary Arterial Hypertension
Official title: A Clinical Trial of Aspirin and Simvastatin in Pulmonary Arterial Hypertension
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE2
Conditions: Hypertension, Pulmonary
Keywords: Pulmonary Arterial Hypertension
Lead sponsor: University of Pennsylvania
Sponsor class: OTHER
Collaborators: name: National Heart, Lung, and Blood Institute (NHLBI)
First posted: 2006-10-06
Enrollment: 64
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: FACTORIAL
Primary purpose: TREATMENT

Brief summary: The purpose of this study is to determine whether aspirin and simvastatin are safe and effective for the treatment of pulmonary arterial hypertension (PAH).

Detailed description: PAH is characterized by dyspnea, fatigue, and lower extremity edema as a result of heart failure. In PAH, in situ thrombosis may occur in the lungs, and pulmonary endothelial dysfunction is well-recognized. As aspirin inhibits platelet aggregation, there may be value in using aspirin to treat PAH. Simvastatin has beneficial effects on blood vessels in other types of cardiovascular disease. Therefore, simvastatin may similarly benefit patients with PAH.

Participants in this study will be randomly assigned to receive 6 months of daily placebo tablets, daily aspirin and daily placebo, daily simvastatin and daily placebo, or daily aspirin and daily simvastatin in a double-blind fashion. The study will compare the safety and efficacy of aspirin to placebo and simvastatin to placebo.

Eligibility criteria: Inclusion Criteria:

* Mean pulmonary artery pressure greater than 25 mm Hg at rest with a pulmonary capillary wedge pressure less than 16 mm Hg
* Diagnosis of PAH that is a) idiopathic, b) familial, or c) associated with collagen vascular disease, HIV infection, congenital systemic-to-pulmonary shunt, or former anorexigen use
* Most recent pulmonary function tests showing FEV1/FVC ratio greater than 50% AND one of the following conditions: a) total lung capacity greater than 70% predicted, or b) total lung capacity between 60% and 70% of predicted value with no more than mild patchy interstitial lung disease on high resolution computerized tomography of the chest
* Ability to perform six-minute walk testing without limitations in musculoskeletal function or coordination
* Negative pregnancy test at screening visit for women of childbearing potential
* If female, willing to use adequate form of birth control

Exclusion Criteria:

* PAH related to other etiologies
* Diagnosis of sickle cell disease
* Clinically significant untreated sleep apnea, as diagnosed by polysomnography
* Left-sided valvular disease (more than moderate mitral valve stenosis or insufficiency or aortic stenosis or insufficiency), pulmonary artery or valve stenosis, or ejection fraction less than 45% on echocardiography
* Hospitalized or acutely ill
* Kidney failure
* Initiation of PAH therapy (prostacyclin analogues, endothelin \[ET\]-1 receptor antagonists, phosphodiesterase \[PDE\]-5 inhibitors) within 3 months of study entry
* Allergy or hypersensitivity to aspirin or simvastatin
* Absolute indication for aspirin or other anti-platelet therapy
* Current treatment with statin therapy
* Inability or unwillingness to avoid non-steroidal, anti-inflammatory medications for 6 months following study entry
* Current or recent use or planned treatment with one of the following: amiodarone, cyclosporine, itraconazole, ketoconazole, erythromycin, clarithromycin, HIV protease inhibitors, nefazodone, cimetidine, danazol, large quantities of grapefruit juice (more than 1 quart daily), verapamil, fibrates, or niacin
* Peptic or duodenal ulcer diagnosed within 1 year of study entry
* Gastrointestinal bleeding within 6 months prior of study entry
* Bleeding diathesis
* History of intracranial bleeding
* Anemia (hematocrit less than 30%) at screening
* International normalized ratio (INR) greater than 3.0 at screening
* Severe thrombocytopenia (less than 75,000/L) at screening
* Hepatic transaminases greater than twice the upper limit of normal at screening
* Chronic liver disease (e.g., cirrhosis, chronic hepatitis) with portal hypertension
* Current or recent (within 6 months of study entry) chronic heavy alcohol consumption
* History of myositis
* Creatine phosphokinase (CPK) greater than 1.5 times the upper limit of normal at screening
* Abnormalities of the arm or hand or past radical mastectomy that might prevent brachial artery ultrasound
* Pregnant or breastfeeding
* Current use of another investigational drug for PAH
* Received a lung transplant

Primary outcomes:
measure: Distance Walked in Six Minutes
timeFrame: Measured at 6 months
Secondary outcomes:
measure: Time to Clinical Worsening Events (Number of Events)
timeFrame: Measured at 6 months
measure: Adverse Events
timeFrame: Measured at 6 months
Other outcomes:
Locations:
city: Baltimore
country: United States
facility: Johns Hopkins University
state: Maryland
city: Boston
country: United States
facility: Tufts University School of Medicine
state: Massachusetts
city: New York
country: United States
facility: Columbia University
state: New York
city: Philadelphia
country: United States
facility: University of Pennsylvania
state: Pennsylvania
Study officials:
affiliation: University of Pennsylvania
name: Steven M Kawut, MD, MS
role: PRINCIPAL_INVESTIGATOR
affiliation: Columbia University
name: David J Lederer, MD, MS
role: PRINCIPAL_INVESTIGATOR
affiliation: Johns Hopkins University
name: Reda E Girgis, MB, BCh
role: PRINCIPAL_INVESTIGATOR
affiliation: Tufts University
name: Kari E Roberts, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Kawut SM, Bagiella E, Lederer DJ, Shimbo D, Horn EM, Roberts KE, Hill NS, Barr RG, Rosenzweig EB, Post W, Tracy RP, Palevsky HI, Hassoun PM, Girgis RE; ASA-STAT Study Group. Randomized clinical trial of aspirin and simvastatin for pulmonary arterial hypertension: ASA-STAT. Circulation. 2011 Jun 28;123(25):2985-93. doi: 10.1161/CIRCULATIONAHA.110.015693. Epub 2011 May 18.
citation: Al-Naamani N, Palevsky HI, Lederer DJ, Horn EM, Mathai SC, Roberts KE, Tracy RP, Hassoun PM, Girgis RE, Shimbo D, Post WS, Kawut SM; ASA-STAT Study Group. Prognostic Significance of Biomarkers in Pulmonary Arterial Hypertension. Ann Am Thorac Soc. 2016 Jan;13(1):25-30. doi: 10.1513/AnnalsATS.201508-543OC.
citation: Matura LA, Ventetuolo CE, Palevsky HI, Lederer DJ, Horn EM, Mathai SC, Pinder D, Archer-Chicko C, Bagiella E, Roberts KE, Tracy RP, Hassoun PM, Girgis RE, Kawut SM. Interleukin-6 and tumor necrosis factor-alpha are associated with quality of life-related symptoms in pulmonary arterial hypertension. Ann Am Thorac Soc. 2015 Mar;12(3):370-5. doi: 10.1513/AnnalsATS.201410-463OC.
citation: Kawut SM, Bagiella E, Shimbo D, Lederer DJ, Al-Naamani N, Roberts KE, Barr RG, Post W, Horn EM, Tracy R, Hassoun P, Girgis R; ASA-STAT Study Group. Rationale and design of a phase II clinical trial of aspirin and simvastatin for the treatment of pulmonary arterial hypertension: ASA-STAT. Contemp Clin Trials. 2011 Mar;32(2):280-7. doi: 10.1016/j.cct.2010.12.005. Epub 2010 Dec 10.