Clinical trial NCT01181284: Modulating Effects of Lisinopril on Sildenafil Activity in Pulmonary Arterial Hypertension(PAH)( MELISSA)
Official title: Modulating Effects of Lisinopril on Sildenafil Activity in PAH (MELISSA)
Study type: OBSERVATIONAL
Overall status: COMPLETED
Conditions: Pulmonary Arterial Hypertension
Keywords: Pulmonary Arterial Hypertension (PAH)
Lead sponsor: Mayo Clinic
Sponsor class: OTHER
First posted: 2010-08-13
Enrollment: 24
Sex: ALL
Minimum age (years): 18
Maximum age (years): 75
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Observational model: COHORT
Time perspective: PROSPECTIVE
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.

Brief summary: 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.

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

Eligibility criteria: 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

Primary outcomes:
measure: The primary aim of the pilot study is to assess feasibility and tolerability.
timeFrame: 32 weeks
Secondary outcomes:
measure: Demonstrate tolerability of long-acting angiotensin-converting enzyme inhibitor (ACEI) therapy in this patient cohort
timeFrame: 32 weeks
measure: Demonstrate whether long-acting angiotensin-converting enzyme inhibitor (ACEI) in Pulmonary Arterial Hypertension (PAH) pts on sildenafil modifies regulation of the genes.
timeFrame: 32 weeks
measure: Demonstrate whether ACEI in PAH pts on sildenafil reduces N-BNP levels, a marker of disease severity
timeFrame: 32 weeks
measure: Demonstrate whether ACEI in PAH pts on sildenafil has an effect on pulmonary gas exchange parameters (exhaled NO, Dm, Vc, DLCO).
timeFrame: 32 weeks
measure: Obtain exploratory data regarding whether ACEI in PAH pts on sildenafil improves functional class and 6 minute walk distance.
timeFrame: 32 weeks
Other outcomes:
Locations:
city: Rochester
country: United States
facility: Mayo Clinic
state: Minnesota
Study officials:
affiliation: Mayo Clinic
name: Robert P Frantz, MD
role: PRINCIPAL_INVESTIGATOR
References: