Modulating Effects of Lisinopril on Sildenafil Activity in Pulmonary Arterial Hypertension(PAH)( MELISSA) (MELISSA)

Modulating Effects of Lisinopril on Sildenafil Activity in PAH (MELISSA)

Patients with pulmonary arterial hypertension(PAH) suffer from chronic shortness of breath, and have impaired survival related to progressive right ventricular failure. Abnormal vasoreactivity to nitric oxide(NO) plays a role in the pathophysiology of PAH. Phosphodiesterase Type 5 Inhibitor (PDE5 inhibitors) sildenafil have been shown to be beneficial in PAH, but extent of benefit is variable.

Study Overview

• Status: Completed
• Conditions: Pulmonary Arterial Hypertension

Detailed Description

The broad aim of this investigation is to determine whether the modulating effect of angiotensin converting enzyme inhibition on vascular smooth muscle responsiveness to the nitric oxide pathway that we have observed in an animal model of Congestive Heart Failure(CHF) can be exploited in humans with PAH. Furthermore, we have identified a group of genes TAO kinase I, IL-10, Rho kinase, Raf1, bile acid coenzyme A and Fmr1 that are modulated by long-acting angiotensin-converting enzyme inhibitor (ACEI) in our animal model, and therefore may also be modulated by ACEI in patients with PAH

• Study Type: Observational
• Enrollment (Actual): 24

Contacts and Locations

Study Locations

• United States
  • Minnesota
    • Rochester, Minnesota, United States, 55905
      • Mayo Clinic

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 75 years (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

• Sampling Method: Probability Sample

Study Population

Participants will be currently diagnosed with Pulmonary Arterial Hypertension (PAH). Lisinopril versus placebo will be added to participants already recieving a stable dose of Sildenafil.

Description

Inclusion Criteria:

• Age 18-75
• World Health Organization (WHO) Group I PAH with prior documentation of peripheral vascular resistance (PVR) > 3 WU and wedge(PCW) 16 or less.
• WHO Functional Class I-III
• 6 minute walk distance 150-575 meters
• Women of child bearing potential must have a negative pregnancy test and be using effective contraception
• Receiving therapy with phosphodiesterase-5 inhibitor for PAH (sildenafil or tadalafil) for at least 3 months and with stable dose for at least 30 days
• If already receiving therapy with endothelin receptor antagonists must have been on therapy for at least 3 months and on stable dose for at least 30 days

Exclusion Criteria:

• Allergy or intolerance to captopril or other angiotensin converting enzyme inhibitors
• Systemic systolic blood pressure less than 100 mm Hg
• Therapy with prostanoids (iloprost, treprostinil, epoprostenol) within preceding 3 months
• Pregnant or breast feeding
• Creatinine > 2.0 mg/dl
• Potassium > 5.0 meq/dl
• Unable to provide informed consent
• TLC or VC <60% predicted
• Untreated obstructive sleep apnea
• LVEF < 40%
• Hb < 10 mg/dL

Study Plan

How is the study designed?

Number of groups / cohorts

1

Cohorts and Interventions

Group / Cohort
Lisinopril; Participants will be randomized 2 to 1 to receive drug versus placebo.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
The primary aim of the pilot study is to assess feasibility and tolerability.	32 weeks

Secondary Outcome Measures

Outcome Measure	Time Frame
Demonstrate tolerability of long-acting angiotensin-converting enzyme inhibitor (ACEI) therapy in this patient cohort	32 weeks
Demonstrate whether long-acting angiotensin-converting enzyme inhibitor (ACEI) in Pulmonary Arterial Hypertension (PAH) pts on sildenafil modifies regulation of the genes.	32 weeks
Demonstrate whether ACEI in PAH pts on sildenafil reduces N-BNP levels, a marker of disease severity	32 weeks
Demonstrate whether ACEI in PAH pts on sildenafil has an effect on pulmonary gas exchange parameters (exhaled NO, Dm, Vc, DLCO).	32 weeks
Obtain exploratory data regarding whether ACEI in PAH pts on sildenafil improves functional class and 6 minute walk distance.	32 weeks

Collaborators and Investigators

• Sponsor: Mayo Clinic

Study record dates

Study Major Dates

• Study Start: May 1, 2008
• Primary Completion (ACTUAL): July 1, 2011
• Study Completion (ACTUAL): July 1, 2011

Study Registration Dates

• First Submitted: January 7, 2010
• First Submitted That Met QC Criteria: August 12, 2010
• First Posted (ESTIMATE): August 13, 2010

Study Record Updates

• Last Update Posted (ESTIMATE): February 7, 2012
• Last Update Submitted That Met QC Criteria: February 3, 2012
• Last Verified: February 1, 2012

More Information

Terms related to this study

• Keywords: Pulmonary Arterial Hypertension (PAH)
• Additional Relevant MeSH Terms: Cardiovascular Diseases; Vascular Diseases; Respiratory Tract Diseases; Lung Diseases; Hypertension, Pulmonary; Hypertension; Pulmonary Arterial Hypertension; Familial Primary Pulmonary Hypertension
• Other Study ID Numbers: 08-001716; MELISSA