A Study to Evaluate the Effectiveness and Safety of Ralinepag To Improve Treatment Outcomes in Peripheral Arterial Hypertension (PAH) Patients

Overview

About this study

The purpose of this study is to identify a unique proteomic signal in the allergic fungal sinusitis mucus compared to bacterial chronic sinusitis and normal healthy mucus samples, to use proteomic approaches to identify and qunantify bone morphogenic proteins and cytokines in the mucus, and to evaluate for return of the signature or bone morphogenic proteins as an early maker for recurrence.

Participation eligibility

Participant eligibility includes age, gender, type and stage of disease, and previous treatments or health concerns. Guidelines differ from study to study, and identify who can or cannot participate. There is no guarantee that every individual who qualifies and wants to participate in a trial will be enrolled. Contact the study team to discuss study eligibility and potential participation.

Inclusion Criteria

Each subject must meet ALL of the following inclusion criteria to be eligible for enrollment into the study:

  • Males or females aged 18-75 years, inclusive.
  • Evidence of a personally signed and dated informed consent document indicating that the subject has been informed of all pertinent aspects of the study prior to initiation of any study-related procedures.
  • Subjects who are willing and able to comply with scheduled visits, treatment plan, laboratory tests, and other study procedures.
  • Diagnosis of symptomatic WHO Group 1 PAH classified by one of the following subgroups:
    • Idiopathic pulmonary arterial hypertension (IPAH);
    • Heritable pulmonary arterial hypertension (HPAH);
    • Drugs and toxins induced based on prior exposure to legal drugs, chemicals, and toxins, such as fenfluramine derivatives, other anorexigens, toxic rapeseed oil, or L-tryptophan. A subject with PAH associated with illegal drug use, such as methamphetamine, may be included if the subject has been abstinent and under the care of the investigator for at least 1 year immediately before Screening, with at least 2 negative urine drug screening examinations performed and available for review by the medical monitor; and, in the investigator’s opinion, is compliant with his or her current medication regimen and overall PAH care.
    • PAH associated with:
      • Connnective tissue disease (CTD);
      • Human immunodeficiency virus (HIV) infection;
      • Congenital systemic-pulmonary shunt (must have undergone surgical correction at least 1 year prior to Screening).
  • Has had a right heart catheterization (RHC) performed at or within 365 days of Screening (RHC will be performed during Screening if not available) that is consistent with the diagnosis of PAH, meeting all of the following criteria:
    • Mean pulmonary arterial pressure (mPAP) ≥25 mmHg (at rest).
    • Pulmonary capillary wedge pressure (PCWP) of:
      •  ≤12 mmHg if pulmonary vascular resistance (PVR) ≥240 to <500 dynes/sec/cm5; OR
      •  ≤15 mmHg if PVR ≥500 dynes/sec/cm5;
      • If PCWP is not available, then left ventricular end diastolic pressure (LVEDP) ≤15 mmHg.
    • PVR >3.00 Wood units or > 240 dynes/sec/cm5.
    • If more than one RHC was performed in the last 365 days prior to Screening, the most recent RHC that includes parameters sufficient to evaluate the above criteria must be used for this assessment.
  • Has WHO/ NYHA functional class II to IV symptoms.
  • If on PAH-specific background therapy, subject is on stable therapy with either an endothelin receptor antagonist (ERA) and/or an agent acting on the nitric oxide (NO) pathway, a phosphodiesterase type 5 (PDE5) inhibitor or a soluble guanylate cyclase (sGC) stimulator. Subjects may be naïve to PAH-specific treatments.
    • Stable is defined as no change in dose or regimen within 90 days of Screening and for the duration of the study.
    • Subjects may be on 1 agent active in the NO pathway, i.e., either a PDE5 inhibitor or an sGC at stable dose (but not both).
    • If the subject’s disease-specific PAH therapy does not include a PDE5 inhibitor, the use of PDE5 inhibitor as needed for erectile dysfunction (ED) is permitted as long as the subject has not taken a dose within 48-hours of any Baseline or study related efficacy assessment. In addition, the subject must not take more than 8 sildenafil tablets, 6 vardenafil, or 4 tadalafil tablets per month for ED.
  • Has a 6MWD of ≥50 meters on two consecutive tests, within 15% of each other, preferably performed on different days during Screening. If both tests are done on the same day, then they must be completed >4 hours apart.
  • If the subject is taking the following concomitant medications that may affect PAH, the subject must be on a stable dose for at least 30 days prior to the start of Screening and the dosage maintained throughout the study.
    • Calcium channel blockers, digoxin, or L-arginine supplementation;
    • If the subject is taking anticoagulants, anticoagulation status must be maintained/stable in the therapeutic range for at least 30 days prior to the start of Screening.
  • Both male and female subjects agree to use a medically acceptable method of contraception throughout the entire study period from informed consent through to the Follow-up Visit, if the possibility of conception exists. Eligible male and female subjects must also agree not to participate in a conception process (i.e., actively attempt to become pregnant or to impregnate, sperm donation, in vitro fertilization) during the study and for 30 days after the last dose of IMP. Medically acceptable methods of contraception include the following:
    • oral, implantable, or injectable contraceptives (starting ≥60 days before dosing) and diaphragm with vaginal spermicide, cervical cap with vaginal spermicide, or male condom;
    • male condom and partner using diaphragm with vaginal spermicide or cervical cap with vaginal spermicide;
    • standard intrauterine device (IUD; e.g., Copper T 380A IUD), intrauterine system (IUS; e.g., LNg 20 IUS - progesterone IUD), progesterone implant, or tubal sterilization (≥180 days after surgery);
    • post vasectomy and male condom, partner using diaphragm with spermicide, cervical cap with spermicide, estrogen and progesterone oral contraceptives ("the pill"), estrogen and progesterone transdermal patch, vaginal ring, or progesterone injection.
  • Women who are surgically sterile or postmenopausal for at least 12 months are not considered to be of childbearing potential. If of childbearing potential, female partners of male study participants should agree to utilize medically acceptable methods of contraception for the duration of study participation.

Exclusion Criteria:

Subjects must not meet ANY of the following exclusion criteria to be eligible for enrollment into the study, unless otherwise indicated:

  • Body weight <40 kg.
  • Body mass index (BMI) ≥40 kg/m2.
  • Group 2 to 5 pulmonary hypertension according to the Nice classification (Simonneau 2013).
  • PAH diagnosis ≥5 years at Screening.
  • For subjects with HIV-associated PAH, any of the following:
    • concomitant active opportunistic infections within 180 days of Screening;
    • detectable viral load at Screening;
    • cluster designation 4 (CD4+) T-cell count <200/mm3 within 90 days of Screening;
    • changes in antiretroviral regimen within 90 days of Screening.
  • Presence of 3 or more of the following risk factors for heart failure with preserved ejection fraction at Screening:
    • BMI >30 kg/m2;
    • Diabetes mellitus of any type;
    • Systemic hypertension;
    • Significant coronary artery disease, i.e., any of the following:
      • Angina;
      • More than 50% stenosis in a coronary artery (by coronary angiography);
      • Previous myocardial infarction;
      • Previous or planned coronary artery bypass grafting and/or coronary artery stenting;
    • Left atrial volume index (LAVi) >30 mL/m2.
  • Echocardiogram (ECHO) within 365 days prior to Screening demonstrating significant left-sided heart disease, including any of the following:
    • Left ventricular ejection fraction (LVEF) <40%;
    • LVEF ≥50% but with impaired left ventricular (LV) relaxation;
    • Mitral valve E/A ratio ≥2; or
    • Average mitral valve E/e’ >14 and LV volume index >34 mL/m2;
    • Moderate or severe left sided valvular disease (aortic or mitral valve stenosis or regurgitation);
    • If more than one ECHO was performed in the last 365 days prior to Screening, the most recent ECHO that includes parameters sufficient to evaluate the above criteria must be used for this assessment.
  • Has a cardiac index (CI) of >3.2 L/min/m2 obtained from a RHC performed at or within 365 days of Screening.
  • Acutely decompensated heart failure within 30 days prior to Screening.
  • Evidence of protocol-defined significant cardiac disease history including, but not limited to, any of the following:
    • Restrictive, dilated or obstructive cardiomyopathy;
    • Percutaneous coronary intervention or coronary artery bypass surgery within 180 days prior to Screening;
    • Any persistent (chronic) or permanent atrial fibrillation.
  • Has evidence of more than mild parenchymal lung disease on pulmonary function tests (PFTs) performed within 180 days prior to Screening. PFTs will be performed as part of Screening procedures, if data within 180 days of Screening are not available. Subjects with any of the following criteria will be excluded:
    • Forced expiratory volume in 1 second (FEV1) <60% (predicted) (pre-bronchodilators); or
    • Forced expiratory volume in 1 second/forced vital capacity ratio (FEV1/FVC) <65% (pre-bronchodilators); or
    • Total lung capacity (TLC) <70% predicted. If the TLC is >60% predicted and <70% predicted, then imaging (i.e., high resolution computed tomography [HRCT]) is required to exclude more than mild parenchymal lung disease. The subject may be enrolled pending review and approval by the medical monitor.
  • Has evidence of thromboembolic disease as determined by ventilation-perfusion (V/Q) lung scan or local standard of care diagnostic evaluation within 5 years of Screening:
    • V/Q scanning is preferred, but if unavailable, spiral/helical/electron beam computed tomography (CT) angiography is acceptable in subjects with NO history of venous thromboembolic disease;
    • If V/Q scan is unavailable and subject has a prior history of venous thromboembolic disease, then selective pulmonary angiography is required to exclude chronic thromboembolic disease;
    • If a V/Q scan is abnormal (i.e., anything other than "normal" or "low probability"), then a selective pulmonary angiography must be conducted to exclude chronic thromboembolic disease;
  • All required tests may be requested for medical monitor review if clinically indicated to exclude chronic thromboembolic pulmonary hypertension.
  • Has obstructive sleep apnea that is symptomatic and/or not treated with stable therapy.
  • Subjects treated with continuous positive airway pressure (CPAP) or bi-level positive airway pressure (BiPAP) must have a sleep study within 180 days of Screening that shows an adequate response (i.e., apnea-hypopnea index [AHI] <7).
  • Uncontrolled systemic hypertension as evidenced by sitting systolic blood pressure (SBP) >160 mmHg or sitting diastolic blood pressure (DBP) >100 mmHg at Screening.
  • Hypotension (SBP <90 mmHg) at Screening.
  • History of orthostatic hypotension or orthostatic hypotension at Screening, defined as a drop in SBP ≥20 mmHg or DBP ≥10 mmHg or the development of significant postural symptoms (syncope, near syncope, lightheadedness, or vertigo) when going from the supine to the standing position.
  • Male subjects with a corrected QT interval using Fridericia’s formula (QTcF) >450 msec and female subjects with QTcF >470 msec on ECG measured at Screening or Baseline.
  • History of atrial septostomy within 180 days prior to Screening.
  • Diagnosis of Down syndrome. Subjects with Down syndrome are excluded due to the high potential of undiagnosed or poorly managed obstructive sleep apnea in this population.
  • Chronic liver disease (i.e., Child-Pugh B or C), portal hypertension, cirrhosis or complications of cirrhosis/portal hypertension (e.g., variceal hemorrhage, encephalopathy or ascites).
  • Confirmed active infection with hepatitis B virus (HBV) or hepatitis C virus (HCV) at Screening.
    • NOTE: Subjects previously infected with HCV who have a negative viral load after receiving a course of curative treatment are allowed.
  • Subjects with alanine aminotransferase (ALT) or aspartate aminotransferase (AST) ≥3 times the upper limit of normal (ULN) or total bilirubin ≥2xULN at Screening.
  • Chronic renal insufficiency as defined by serum creatinine >2.5 mg/dL or estimated glomerular filtration rate (eGFR) <30 mL/min (calculated using the Modification of Diet in Renal Disease [MDRD] equation) at Screening or the subject requires dialytic support.
  • Hemoglobin concentration <9 g/dL at Screening.
  • Subject required use of intravenous (i.v.) inotropes including, but not limited to, levosimendan, dopamine, dobutamine, dopexamine, epinephrine, isoprenaline (isoproterenol), norepinephrine (noradrenaline), milrinone, or amrinone, within 30 days prior to Screening.
  • Subject has pulmonary veno-occlusive disease.
  • Malignancy within 5 years of Screening, with the exception of localized non-metastatic basal cell carcinoma of the skin and in-situ carcinoma of the cervix excised with curative intent.
  • Recent history (i.e., within 1 year prior to Screening) of alcohol or drug abuse.
  • Subject tests positive for amphetamine, cocaine, methamphetamine, methylenedioxymethamphetamine or phencyclidine in urine drug screen performed at Screening.
  • Initiation of a cardio-pulmonary rehabilitation program based upon exercise within 90 days prior to Screening and/or planned during study participation.
  • Prior participation in any study of ralinepag or participation in another interventional clinical study within 60 days prior to Screening. Concurrent participation in registry or observational studies is allowed, as long as the subject can fulfill all other entry criteria and comply with all study procedures.
  • Any reason that, in the opinion of the investigator or medical monitor, precludes the subject from participating in the study (e.g., any previous or intercurrent medical condition) that may increase the risk associated with study participation or that would confound study analysis or impair study participation or cooperation.
  • Life expectancy <12 months.

   

Participating Mayo Clinic locations

Study statuses change often. Please contact the study team for the most up-to-date information regarding possible participation.

Mayo Clinic Location Status Contact

Scottsdale/Phoenix, Ariz.

Mayo Clinic principal investigator

Robert Scott, M.D., Ph.D.

Open for enrollment

Contact information:

Vy Nguyen

(480)342-6428

Nguyen.Vy1@mayo.edu

More information

Publications

Publications are currently not available

Study Results Summary

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Supplemental Study Information

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