Study of Angiogenic Cell Therapy for Progressive Pulmonary Hypertension: Intervention With Repeat Dosing of eNOS-enhanced EPCs (SAPPHIRE)

A Multicentre, Late Phase Clinical Trial to Establish the Efficacy and Safety of Repeat Dosing of Autologous Endothelial Progenitor Cells (EPCs) Transfected With Human Endothelial NO-synthase (eNOS) in Patients With Pulmonary Arterial Hypertension (PAH) on Top of Conventional Treatments

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.

Study Overview

• Status: Active, not recruiting
• Conditions: Hypertension,Pulmonary
• Intervention / Treatment: Biological: Placebo followed by Autologous EPCs transfected with human eNOS; Biological: Autologous EPCs transfected with human eNOS followed by Placebo; Biological: Autologous EPCs transfected with human eNOS

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Actual): 12
• Phase: Phase 2; Phase 3

Contacts and Locations

Study Locations

• Canada
  • Alberta
    • Calgary, Alberta, Canada, T1Y 6J4
      • Peter Lougheed Center, University of Calgary
  • Ontario
    • London, Ontario, Canada, N6A 5W9
      • London Health Sciences Center
    • Ottawa, Ontario, Canada, K1Y 4W7
      • University of Ottawa Heart Institute
    • Toronto, Ontario, Canada, M5G 2N2
      • Toronto General Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 80 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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
• 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 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-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 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 MI
    • History of PCI
    • Prior coronary angiography evidence of CAD (>50% stenosis in ≥1 vessel)
    • Previous positive Stress Test
    • Previous 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 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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: Triple

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Placebo followed by Autologous EPCs transfected with eNOS; 4 monthly IV injections of Placebo (Plasma-Lyte A) during Course 1 followed by 4 monthly IV injections of Autologous EPCs transfected with human eNOS (total of 80 million cells) during Course 2	Biological: Placebo followed by Autologous EPCs transfected with human eNOS; 4 doses of placebo in first 6 months followed by 4 doses of autologous EPCs transfected with eNOS in second 6 months
Experimental: Autologous EPCs transfected with eNOS followed by Placebo; 4 monthly IV injections of Autologous EPCs transfected with human eNOS (total of 80 million cells) during Course 1 followed by 4 monthly IV injections of Placebo (Plasma-Lyte A) during Course 2	Biological: Autologous EPCs transfected with human eNOS followed by Placebo; 4 doses of autologous EPCs transfected with eNOS in first 6 months followed by 4 doses of placebo in second 6 months
Experimental: Autologous EPCs transfected with eNOS; 4 monthly IV injections of Autologous EPCs transfected with human eNOS in Course 1 followed by 4 monthly injections of Autologous EPCs transfected with human eNOS in Course 2 (total of 160 million cells)	Biological: Autologous EPCs transfected with human eNOS; 4 doses of autologous EPCs transfected with eNOS in first 6 months which is repeated in second 6 months

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in 6 Minute Walk Distance (6MWD) from Baseline	Comparison of change from baseline after delivery of 4 doses of study product (Arms 2 and 3 versus Arm 1)	6 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in 6 Minute Walk Distance (6MWD) from Baseline	Comparison of change from baseline after delivery of 4 versus 8 doses of study product (Arms 1 versus Arm 3)	12 months
Change in 6 Minute Walk Distance (6MWD) from Baseline	Comparison of change from baseline to assess durability of any measured improvement (Arm 2 only)	3 and 9 months
Change in Pulmonary Vascular Resistance from Baseline	Comparison of change from baseline after 4 doses of study product (Arms 2 and 3 versus Arm 1)	6 months
Change in Pulmonary Vascular Resistance from Baseline	Comparison of change from baseline after delivery of 4 versus 8 doses of study product (Arm 1 versus Arm 3)	12 months
Change in Pulmonary Vascular Resistance from Baseline	Comparison of change from baseline to assess durability of any measured improvement (Arm 2 only)	3 and 9 months
Number of Deaths or Clinical Worsening of Pulmonary Arterial Hypertension	Comparision of number measured from baseline (Arms 2 and 3 versus Arm 1). Clinical worsening will be defined by any of the following: all-cause mortality, hospitalization due to worsening cardiopulmonary status attributable to progression of disease, decrease in 6MWD by ≥ 15%, worsening of WHO functional class	6 months
Number of Deaths or Clinical Worsening of Pulmonary Arterial Hypertension	Comparison of number measured from baseline after delivery of 4 versus 8 doses of study product (Arm 1 versus Arm 3). Clinical worsening will be defined by any of the following: all-cause mortality, hospitalization due to worsening cardiopulmonary status attributable to progression of disease, decrease in 6MWD by ≥ 15%, worsening of WHO functional class	12 months
Change in Echocardiography Right Ventricular (RV) Function Measures from Baseline	Comparison of change from baseline after 4 doses of study product (Arms 2 and 3 versus Arm 1)	6 months
Change in Echocardiography Right Ventricular (RV) Function Measures from Baseline	Comparison of change from baseline after delivery of 4 versus 8 doses of study product (Arm 1 versus Arm 3)	12 months
Change in Magnetic Resonance Imaging Right Ventricular (RV) Function Measures from Baseline	Comparison of change from baseline after delivery of 4 doses of study product (Arms 2 and 3 versus Arm 1)	6 months
Change in Magnetic Resonance Imaging Right Ventricular (RV) Function Measures from Baseline	Comparison of change from baseline after delivery of 4 versus 8 doses of study product (Arm 1 versus Arm 3)	12 months
Change in Quality of Life Measures from Baseline	Comparison of change from baseline measured by SF-36 Survey after delivery of 4 doses of study product (Arms 2 and 3 versus Arm 1)	6 months
Change in Quality of Life Measures from Baseline	Comparison in change from baseline measured by SF-36 Survey after delivery of 4 versus 8 doses of study product (Arm 1 versus Arm 3)	12 months

Collaborators and Investigators

• Sponsor: Northern Therapeutics
• Collaborators: Ottawa Hospital Research Institute

Study record dates

Study Major Dates

• Study Start (Actual): September 28, 2017
• Primary Completion (Actual): November 1, 2023
• Study Completion (Estimated): December 1, 2033

Study Registration Dates

• First Submitted: December 15, 2016
• First Submitted That Met QC Criteria: December 19, 2016
• First Posted (Estimated): December 23, 2016

Study Record Updates

• Last Update Posted (Estimated): February 1, 2024
• Last Update Submitted That Met QC Criteria: January 30, 2024
• Last Verified: January 1, 2024

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Cardiovascular Diseases; Vascular Diseases; Respiratory Tract Diseases; Lung Diseases; Hypertension; Hypertension, Pulmonary
• Other Study ID Numbers: CT-PAH002

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No