A Study of Ranolazine Acute Administration and Short Term Administration in Pulmonary Arterial Hypertension

Sponsor

University of Chicago (Other)

Overall Status

Completed

CT.gov ID

NCT01757808

Collaborator

(none)

Enrollment

Location

Arms

Duration (Months)

0.3

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

The purpose of this study is to assess the safety of ranolazine in people with pulmonary arterial hypertension (PAH) and who are receiving 1 or more background PAH therapies: ambrisentan, sildenafil,tadalafil, epoprostenol, treprostinil (IV, SC, inhaled), or iloprost.

The primary objective is:

To estimate the effect of ranolazine administration on acute hemodynamics.
To assess safety of ranolazine acutely over 6 hrs in the catheterization lab and after 12 weeks of therapy
To assess changes in right ventricular function after 12 weeks of therapy.

Condition or Disease	Intervention/Treatment	Phase
Pulmonary Arterial Hypertension	Drug: Ranolazine Drug: Placebo	Phase 1

Detailed Description

Pulmonary arterial hypertension is a medical disorder in which pressure in the blood vessels going from the right side of the heart to the lungs is higher than normal. The increased blood pressure in the lungs places a strain on the heart. This strain causes the heart to pump less blood into the lungs, causing physical symptoms of shortness of breath and tiredness. The added strain to the heart can cause physical symptoms of swelling in the feet and abdomen. These symptoms can get worse over time due to the decreased pumping ability of the heart.

This study will use a drug called ranolazine. This drug has been approved by the Food and Drug Administration (FDA) to treat chronic angina (chest pain). However, since it has not been approved for use in PAH its use in this study is considered experimental.

Study Design

Study Type:

Interventional

Actual Enrollment :

12 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

Double (Participant, Investigator)

Primary Purpose:

Treatment

Official Title:

A Phase I Study of Ranolazine Acute Administration and Short Term Administration in Pulmonary Arterial Hypertension

Study Start Date :

Aug 1, 2011

Actual Primary Completion Date :

Jan 1, 2015

Actual Study Completion Date :

Jan 1, 2015

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Ranolazine	Drug: Ranolazine ranolazine sustained release at a dose of 500mg for one month followed by a dose of 1000mg. Other Names: GS-9668
Placebo Comparator: Placebo	Drug: Placebo placebo at a dose of 500mg for one month followed by a dose of 1000mg. Other Names: sugar pill

Arm

Intervention/Treatment

Experimental: Ranolazine

Drug: Ranolazine

ranolazine sustained release at a dose of 500mg for one month followed by a dose of 1000mg.

Other Names:

GS-9668

Placebo Comparator: Placebo

Drug: Placebo

placebo at a dose of 500mg for one month followed by a dose of 1000mg.

Other Names:

sugar pill

Outcome Measures

Primary Outcome Measures

Change in pulmonary vascular resistance (PVR) [12 weeks]

Secondary Outcome Measures

Change in CPET (VE/VCO2, PETCO2, peak VO2, peak HR, peak RER, work max (MET or Watt), sub maximum exercise time [12 weeks]
Change in RV echo parameters: 2D, 3D [12 weeks]
Change in 6MWD [12 weeks]
Safety/SAE [12 weeks]
AE and SAE on study drug and acutely changes in blood pressure and PAP

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years to 72 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

All subjects age 18-72 yrs will have a diagnosis of PAH. PAH as defined as idiopathic PAH, heritable PAH or PAH associated with collagen vascular disease, congenital heart disease (repaired), or anorexigen use. A history of PAH as defined by hemodynamics at diagnosis by right heart catheterization defined as: mean PAP >25 mmHg with a normal PCWP < 15 mm Hg at rest and a PVR >3 Wood units.
Baseline 6MW >150 meters
Patients will be receiving FDA approved PAH monotherapy or dual therapy medications: including, ambrisentan (5,10mg), sildenafil (60-240mg), tadalafil (40mg), epoprostenol, treprostinil, or iloprost at stable doses for >90days.
Receiving conventional therapy as clinically indicated (oxygen, calcium channel blockers, digoxin) with dose that is unchanged in the preceding 30 days prior to enrollment. This is excluding anticoagulants (warfarin) as the patient's dose may not be stable if the patient is having a cardiac catheterization at baseline within 30 days of enrollment and warfarin is being held.

Exclusion Criteria:

PAH Category II-IV and Category I associated with all other etiologies: HIV, portopulmonary disease
All subjects on monotherapy calcium blockers as "calcium blocker responders" irrespective of therapy
All subjects receiving CY3P4 inducer (i.e. bosentan)
Subjects with pulmonary hypertension due to significant interstitial lung disease, chronic obstructive pulmonary disease, congestive heart failure, valvular heart disease
Subjects with (World Health Organization (WHO) functional Class I or Class IV
Subjects with total lung capacity (TLC) < 60% of predicted
Subjects with significant obstructive lung disease with FEV1/FVC ratio < 70% of predicted
Subjects with hypotension defined as systolic arterial pressure < 90 mmHg at baseline
Subjects with hypertension defined as systolic arterial pressure >140 mmHg at baseline and a diastolic arterial pressure > 90 mmHg despite adequate medical therapy.
Subjects with impaired renal function as defined as estimated glomerular filtration rate (eGFR) less than 45 mL/min/BSA (where BSA=1.73m2) as calculated by the

Modification of Diet in Renal Disease (MDRD) equation:

Patients with eGFR 45-50 mL/min/BSA may be enrolled only after discussion with data safety monitoring board. Patients with eGFR ≥ 50 mL/min/BSA may be enrolled without such a discussion.

Subjects with liver function tests (transaminases (AST/ALT), total bilirubin, and alkaline phosphatase) >2X normal values
Subjects with acutely decompensated heart failure requiring hospitalization or medication adjustment or hospitalization for any cause within the previous 30 days prior to screening
Subjects may not be receiving any other investigational agents
Subjects with left ventricular ejection fraction <45% or left ventricular shortening fraction <0.2
Subjects with acute myocardial infarction within 90 days prior to screening
Subjects taking nitrates for any medical problem
Subjects with a recent (<180 days) history of pulmonary embolism verified by ventilation/perfusion scan, angiogram or spiral CT scan
Pregnant or lactating women
Subjects with a history of current drug abuse including alcohol
History of gastric bypass surgery
History of sinus or atrioventricular nodal disease ie. sick sinus syndrome, or second or third degree heart block.