Study of Angiogenic Cell Therapy for Progressive Pulmonary Hypertension

The SAPPHIRE clinical trial seeks to establish the efficacy and safety of repeated monthly dosing of autologous EPCs transfected with human eNOS (heNOS) in patients with symptomatic severe PAH on available PAH-targeted medical therapy.

SAPPHIRE will use autologous progenitor cell-based gene delivery to enhance lung microvascular repair and regeneration in patients with severe symptomatic PAH. A total of 45 patients will be enrolled in this multi-centre, late phase, randomized, double-blind, placebo-controlled, 3-arm protocol. Up to nine centres across Canada will participate.

Consented study participants who meet all eligibility criteria during the screening period will be scheduled to undergo apheresis. Following successful apheresis collection and receipt of the cell samples by the cell manufacturing facility, randomization will take place though a web-based system. Manufacturing of the cell therapy product will then be performed by the cell manufacturing facility according to the assigned treatment allocation:

Arm 1: Placebo (Plasma-Lyte A; 4 monthly IV infusions) in Course 1 (1st 6 months) followed by Autologous EPCs transfected with human eNOS in Course 2 (2nd 6 months; 4 monthly IV infusions)

Arm 2: Autologous EPCs transfected with human eNOS in Course 1 (1st 6 months; 4 monthly IV infusions) followed by Placebo (Plasma-Lyte A) in Course 2 (2nd 6 months; 4 monthly IV infusions)

Arm 3: Autologous EPCs transfected with human eNOS in Course 1 (1st 6 months; 4 monthly IV infusions) followed by a repeat dosing with Autologous EPCs transfected with human eNOS in Course 2 (2nd 6 months; 4 monthly IV infusions)

Approximately 5-9 days later, the study product will be transported to the investigative site where the initial treatment will be delivered to the study participant in an outpatient setting which is equipped for continuous monitoring of vital signs and oxygen saturation. Participants will subsequently be monitored for a minimum of 1 hour and discharged from the clinic once judged by the study investigator to be clinically stable.

Treatment and follow-up assessments will take place over a 12-month period (11 study visits in total). Once the 12-month trial data collection is completed, the trial will convert to a registry with the goal of collecting long-term safety information through annual telephone contacts for 10 years. Participants will be permitted to enroll in other clinical trials during the registry period.

Eligibility Criteria:
Inclusion Criteria:

* Age ≥ 18 years, ≤ 80 years
* Established diagnosis of PAH due to the following:

  * Idiopathic or heritable PAH;
  * Scleroderma associated PAH (limited or diffuse);
  * Drugs (anorexigens) or toxins;
  * Congenital heart defects (atrial septal defects, ventricular septal defects, and patent ductus arteriosus) repaired ≥ 1 years
* World Health Organization (WHO) functional class II, III, or IV on appropriate stable therapy for PAH for at least 3 months prior to the screening period and up until randomization, apart from modification of anticoagulant or diuretic dosages, or small adjustments in prostaglandin dose that are considered by the Investigator to be consistent with stable parenteral therapy.
* Able to walk unassisted (oxygen use allowed). Aids for carrying oxygen (such as a wheel chair or walker) are permitted provided they are not also required as mobility aids.
* An average 6-Minute Walk Distance (6MWD) of ≥ 125 meters and ≤ 440 meters on two consecutive tests during the Screening period
* Previous diagnostic right heart cardiac catheterization (RHC) at the time of PAH diagnosis with findings consistent with PAH: specifically, mean pulmonary arterial pressure (mPAP) ≥ 25 mmHg (at rest); pulmonary vascular resistance (PVR) ≥ 3 WU; pulmonary capillary wedge pressure (PCWP) (or left ventricular end diastolic pressure) ≤12 mmHg if PVR ≥ 3 to \< 5 Woods Units (WU), or pulmonary capillary wedge pressure (PCWP) (or left ventricular end diastolic pressure) ≤ 15 mmHg if PVR ≥ 5 WU. If repeat testing has occurred since initial diagnosis, the most recent results should be used.
* Echocardiography performed within 12 months prior to the Screening Period confirming a left atrial volume index (LAVI) of ≤ 34 ml/m2 and the absence of any clinically significant left heart disease including evidence of more than mild left-sided valvular heart disease, systolic or diastolic left ventricular dysfunction
* Ventilation and perfusion (VQ) nuclear scan performed as part of the initial workup to establish the diagnosis of PAH showing absence (i.e. low probability) of pulmonary embolism. If repeat testing has occurred since initial diagnosis, the most recent results should be used. In the absence of a VQ scan to establish eligibility, a CT angiogram that has been reviewed by a radiologist with expertise in the work up for pulmonary endarterectomy and deemed negative for chronic thromboembolic disease may be used instead.
* Pulmonary function tests conducted within 2 years prior to the Screening Period to confirm: total lung capacity (TLC) ≥ 65% the predicted value; and forced expiratory volume at one second (FEV1) of ≥ 65% the predicted value
* Must have a resting arterial oxygen saturation (SaO2) ≥88% with or without supplemental oxygen as measured by pulse oximetry at the Screening Visit
* Must not be enrolled in an exercise training program for pulmonary rehabilitation within 3 months prior to the Screening Visit and must agree not to enroll in an exercise training program for pulmonary rehabilitation during the Screening Period and the first 6 months of the study. Participants enrolled in an exercise program for pulmonary rehabilitation 3 months prior to screening may enter the study if they agree to maintain their current level of rehabilitation for the first 6 months of the study
* Women of child-bearing potential (defined as less than 1 year post-menopausal and not surgically sterile) must be practicing abstinence or using two highly effective methods of contraception (defined as a method of birth control that results in a low failure rate, i.e., less than 1% per year, such as approved hormonal contraceptives, barrier methods \[such as a condom or diaphragm\] used with a spermicide, or an intrauterine device). Subjects must have a negative ß-human chorionic gonadotropin (hCG) pregnancy test during the Screening period and negative urine pregnancy test results at all other study visits
* Must be willing and able to comply with study requirements and restrictions.

Exclusion Criteria:

* Pregnant or lactating
* PAH related to any condition not covered under inclusion criteria, including but not limited to pulmonary venous hypertension, pulmonary veno-occlusive disease, pulmonary capillary hemangiomatosis, or chronic thromboembolic pulmonary hypertension
* Evidence of more than mild interstitial lung disease on Chest CT within the last 5 years (last 3 years for patients with scleroderma associated PAH)
* Treatment with an investigational drug, device or therapy within 3 months prior to the screening period or is scheduled to receive an investigational drug, device or therapy during the course of the study
* Any musculoskeletal disease or any other disease that would significantly limit ambulation
* Unrepaired or recently repaired (\< 1 year) congenital systemic-to-pulmonary shunt other than patent foramen ovale
* Patients having three or more of the following four AMBITION study heart failure preserved ejection fractio (HFpEF) risk factors will be excluded:

  * BMI ≥ 30 kg/m2,
  * History of essential hypertension,
  * Diabetes mellitus (any type)
  * Historical evidence of significant coronary artery disease (CAD) by any one of the following:

    * History of myocardial infarction (MI)
    * History of percutaneous coronary intervention (PCI)
    * Prior coronary angiography evidence of CAD (\>50% stenosis in ≥1 vessel)
    * Previous positive Stress Test
    * Previousoronary artery bypass grafting (CABG)
    * Stable angina
* Creatinine clearance \<30 ml/min (using the Cockroft-Gault formula) or requires hemodialysis
* Inability to undergo the apheresis procedure due to poor venous access or laboratory tests that are not within acceptable ranges (not including international normalized ratio (INR) for patients on Coumadin)
* Childs-Pugh class C liver cirrhosis
* Previous atrial septostomy
* Any other clinically significant illness or abnormal laboratory values (measured during the screening period) that, in the opinion of the Investigator, might put the subject at risk of harm during the study or might adversely affect the interpretation of the study data
* Anticipated survival less than 1 year due to concomitant disease
* History of cancer in the past 5 years (except for low grade and fully resolved non-melanoma skin cancer)
* Results during screening consistent with current infection with HIV, Hepatitis B (HBV) or C (HCV), human T-cell lymphotropic virus (HTLV- I/II) or syphilis
* Systemic arterial systolic blood pressure \< 85 mm Hg
* Known allergy to gentamicin or amphotericin
* Patients who have participated in any gene therapy study or an angiogenic growth factor protein study
* Patients unable to provide informed consent and comply with the visit schedule.