Study of Ranolazine in the Treatment of Pulmonary Hypertension Associated With Diastolic Left Ventricular Dysfunction
Condition: Pulmonary Hypertension; Diastolic Left Ventricular Dysfunction
MeSH terms: Hypertension, Pulmonary; Hypertension; Ventricular Dysfunction; Ventricular Dysfunction, Left
Intervention: Ranolazine
Intervention description: Single arm- ranolazine, initiated at 500 mg BID and increased to 1000 mg BID as tolerated
Intervention MeSH terms: Ranolazine
Phase: Phase 4
Study type: Interventional
Primary purpose: Treatment
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 10.0
Sex: All
Minimum age: 18 Years
Maximum age: 75 Years
Healthy volunteers: No
Keywords: pulmonary hypertension; diastolic dyfunction

Summary:

      This is a single center, open-label trial designed to assess the safety and efficacy of
      ranolazine (Ranexa) in patients with pulmonary hypertension associated with left ventricular
      diastolic dysfunction. All patients will receive active drug. The study includes a screening
      period, 6 month treatment period and a follow up period. Eligible patients who provide
      informed consent and who meet all inclusion/exclusion criteria will be enrolled in this
      study.

      There is neither proven therapy for patients with diastolic dysfunction-associated pulmonary
      hypertension nor for patients with diastolic dysfunction alone. Ranolazine, an inhibitor of
      cardiac repolarization (sodium channels), could represent a new and effective treatment of
      this entity.
    

Eligibility criteria:

        Inclusion Criteria:

          -  Written consent prior to any study procedure

          -  Men or women, ages 18 to 75 years

          -  Suspicion of Pulmonary Hypertension by echo (RVSP ≥ 50mmHg) or diagnosis of Pulmonary
             Hypertension by cardiac cath (mPAP ≥25 mmHg at rest)

          -  LVEF ≥50%, (by ECHO, radionuclide imaging, or cardiac cath)

          -  6MWT distance ≥150m and ≤450m at both time points within the Screening Period

          -  NYHA/WHO functional class II-III

          -  RHC measurements on Study Day 1: 1) mean pulmonary artery pressure (MPAP) ≥25 mmHg; 2)
             pulmonary artery occlusion pressure (PAOP) ≥18 mmHg and ≤30 mmHg; 3) pulmonary artery
             diastolic pressure (PADP) - PAOP ≤10 mmHg

        Exclusion Criteria:

          -  Presence or history of any of the following cardiovascular co-morbidities or
             conditions: Hypotension at Screening (defined as a resting SBP≤90mmHg). Hypertension
             at Screening (defined as resting SBP ≥200mmHg), Unstable cardiovascular disease
             including paroxysmal atrial fibrillation or unstable angina, Amyloidosis, hypertrophic
             obstructive cardiomyopathy, restrictive cardiomyopathy, or constrictive pericarditis,
             History of myocardial infarction, coronary artery bypass graft surgery, or
             percutaneous cardiac intervention, Significant valvular heart disease, Cerebrovascular
             accident or transient ischemic attack

          -  Exercise tolerance limited by non-cardiac causes (exercise-induced asthma, malignancy,
             obesity, musculoskeletal disorder).

          -  Clinically significant psychiatric, addictive (DSM-IV criteria), neurologic disease or
             condition that would compromise his/her ability to give informed consent, participate
             fully in this study, or prevent adherence to the protocol

          -  Any other condition or co-morbidity that, in the opinion of the Investigator, would
             compromise his/her ability to give informed consent, participate fully in this study,
             or prevent adherence to the protocol

          -  Clinically significant laboratory abnormalities, including: Positive Hep B surface
             antigen or Hep C antibody, Positive HIV test within one year of Study Day 1, Serum
             alanine aminotransferase (ALT) ≥ 2.0 x ULN, Total bilirubin ≥ 1.2 x ULN (unless
             evidence of Gilbert's syndrome). Serum creatinine ≥ 2.5mg/dL (or calculated creatinine
             clearance less than or equal to 30mL/min). Hemoglobin less than or equal to 10g/dL
             (subject may qualify for the study following diagnosis and treatment of anemia, if the
             anemia is due to iron and/or vitamin deficiency).

        Patients with moderate or severe hepatic impairment (Child-Pugh Classes B or C) or
        requiring hemidialysis.

          -  Subject has received any other investigational medication within the 30 days prior to
             Screening

          -  Prior treatment with ranolazine

          -  Pregnancy or lactation

          -  Women of childbearing potential and men without vasectomies who are not using barrier
             method of contraception

          -  Subject has the presence, or history, of malignancy that required significant medical
             intervention within the preceding 3 months and/or is likely to result in death within
             the next 2 years (exception of basal cell, non-metastatic squamous cell carcinoma of
             the skin, and carcinoma in-situ of the cervix)

          -  Treatment for pulmonary hypertension with epoprostenol (Flolan), treprostinil
             (Remodulin), iloprost (Ventavis), bosentan (Tracleer), ambrisentan (Letairis),
             sildenafil (Revatio), tadalafil (Adcirca). The use of sildenafil, tadalafil, or
             vardenafil is prohibited for any reason within 7 days of hemodynamic assessments on
             Days 1 and 180).

          -  Patients with QTc > 500 msec at baseline

          -  Treatment with potent CYP3A inhibitors, including ketoconazole, itraconazonle,
             clarithromycin, nefazodone, nelfinavir, indinavir, & saquinavir

          -  Treatment with CYP3A inducers, including rifampin, rifabutin, rifapentin,
             phenobarbital, phenytoin, carbamazepine, and St. John's wort.