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Trial record 7 of 11 for:    CARDIOVASCULAR SAPPHIRE

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

This study is not yet open for participant recruitment. (see Contacts and Locations)
Verified December 2016 by Northern Therapeutics
Sponsor:
Collaborator:
Ottawa Hospital Research Institute
Information provided by (Responsible Party):
Northern Therapeutics
ClinicalTrials.gov Identifier:
NCT03001414
First received: December 15, 2016
Last updated: December 19, 2016
Last verified: December 2016
  Purpose
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.

Condition Intervention Phase
Hypertension,Pulmonary
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
Phase 2

Study Type: Interventional
Study Design: Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Double Blind (Participant, Care Provider, Investigator)
Primary Purpose: Treatment
Official Title: A Multicentre, Phase 2 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

Resource links provided by NLM:


Further study details as provided by Northern Therapeutics:

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


Secondary Outcome Measures:
  • Change in 6 Minute Walk Distance (6MWD) from Baseline [ Time Frame: 12 months ]
    Comparison of change from baseline after delivery of 4 versus 8 doses of study product (Arms 1 versus Arm 3)

  • Change in 6 Minute Walk Distance (6MWD) from Baseline [ Time Frame: 3 and 9 months ]
    Comparison of change from baseline to assess durability of any measured improvement (Arm 2 only)

  • Change in Pulmonary Vascular Resistance from Baseline [ Time Frame: 6 months ]
    Comparison of change from baseline after 4 doses of study product (Arms 2 and 3 versus Arm 1)

  • Change in Pulmonary Vascular Resistance from Baseline [ Time Frame: 12 months ]
    Comparison of change from baseline after delivery of 4 versus 8 doses of study product (Arm 1 versus Arm 3)

  • Change in Pulmonary Vascular Resistance from Baseline [ Time Frame: 3 and 9 months ]
    Comparison of change from baseline to assess durability of any measured improvement (Arm 2 only)

  • Number of Deaths or Clinical Worsening of Pulmonary Arterial Hypertension [ Time Frame: 6 months ]
    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

  • Number of Deaths or Clinical Worsening of Pulmonary Arterial Hypertension [ Time Frame: 12 months ]
    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

  • Change in Echocardiography Right Ventricular (RV) Function Measures from Baseline [ Time Frame: 6 months ]
    Comparison of change from baseline after 4 doses of study product (Arms 2 and 3 versus Arm 1)

  • Change in Echocardiography Right Ventricular (RV) Function Measures from Baseline [ Time Frame: 12 months ]
    Comparison of change from baseline after delivery of 4 versus 8 doses of study product (Arm 1 versus Arm 3)

  • Change in Magnetic Resonance Imaging Right Ventricular (RV) Function Measures from Baseline [ Time Frame: 6 months ]
    Comparison of change from baseline after delivery of 4 doses of study product (Arms 2 and 3 versus Arm 1)

  • Change in Magnetic Resonance Imaging Right Ventricular (RV) Function Measures from Baseline [ Time Frame: 12 months ]
    Comparison of change from baseline after delivery of 4 versus 8 doses of study product (Arm 1 versus Arm 3)

  • Change in Quality of Life Measures from Baseline [ Time Frame: 6 months ]
    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)

  • Change in Quality of Life Measures from Baseline [ Time Frame: 12 months ]
    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)


Estimated Enrollment: 45
Study Start Date: April 2017
Estimated Study Completion Date: April 2021
Estimated Primary Completion Date: October 2020 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
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
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
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

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, phase II, randomized, double-blind, placebo-controlled, 3-arm protocol. Up to seven 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

Ages Eligible for Study:   18 Years to 80 Years   (Adult, Senior)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Age ≥ 18 years, ≤ 80 years
  • Established diagnosis of pulmonary arterial hypertension due to the following:

    • Idiopathic or hereditable 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.
  • Able to walk unassisted (oxygen use allowed).
  • An average 6-Minute Walk Distance (6MWD) of ≥ 125 meters and ≤ 400 meters on two consecutive tests during the Screening period.
  • Previous diagnostic right heart cardiac catheterization (RHC) within the last five years with findings consistent with PAH: specifically, mean pulmonary arterial pressure (mPAP) ≥ 25 mmHg (at rest); pulmonary capillary wedge pressure (PCWP) (or left ventricular end diastolic pressure) ≤15 mmHg, and pulmonary vascular resistance (PVR) >5 WU.
  • Echocardiography performed within 6 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 within the last five years showing absence (i.e. low probability) of pulmonary embolism.
  • Pulmonary function tests conducted within 12 months prior to the Screening Period to confirm: total lung capacity (TLC) ≥ 70% the predicted value; and forced expiratory volume at one second (FEV1) of ≥ 70% 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 result 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.
  • 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.
  • Historical evidence of significant coronary arterial disease (CAD) by ANY ONE of the following:

    • History of MI
    • History of PCI
    • Angiographic evidence of CAD (>50% stenosis in ≥1 vessel)
    • Positive Stress Test
    • Previous CABG
    • Stable angina
  • If no significant CAD, participants with ALL THREE of the remaining AMBITION study HFpEF risk factors will be excluded:

    • BMI ≥ 30 kg/m2,
    • AND History of essential hypertension,
    • AND Diabetes mellitus (any type)
  • 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)
  • A history of human immunodeficiency virus (HIV) or hepatitis B or C infection
  • 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
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT03001414

Contacts
Contact: Duncan J Stewart, MD FRCPC 613-737-8899 ext 79017 djstewart@ohri.ca
Contact: Kim Danovitch, CCRP 613-798-5555 ext 17923 kdanovitch@ohri.ca

Locations
Canada, Alberta
University of Alberta Hospital Not yet recruiting
Edmonton, Alberta, Canada, T6G 2B7
Contact: Evangelos Michelakis, MD FACC FAHA    780-407-8822    em2@ualberta.ca   
Principal Investigator: Evangelos Michelakis, MD FACC FAHA         
Canada, British Columbia
Vancouver General Hospital Not yet recruiting
Vancouver, British Columbia, Canada, V5Z 1M9
Contact: John Swiston, MD MPH FRCPC    604 875 4122    swiston@mail.ubc.ca   
Principal Investigator: John Swiston, MD MPH FRCPC         
Canada, Ontario
London Health Sciences Center Not yet recruiting
London, Ontario, Canada, N6A 5W9
Contact: Sanjay Mehta, MD FRCPC    519-667-6723    sanjay.mehta@lhsc.on.ca   
Principal Investigator: Sanjay Mehta, MD FRCPC         
University of Ottawa Heart Institute Not yet recruiting
Ottawa, Ontario, Canada, K1Y 4W7
Contact: George Chandy, MD MSc FRCPC    613-761-5396    gchandy@toh.ca   
Principal Investigator: George Chandy, MD MSc FRCPC         
Toronto General Hospital Not yet recruiting
Toronto, Ontario, Canada, M5G 2N2
Contact: John Granton, MD FRCPC    416-340-4485    john.granton@uhn.ca   
Principal Investigator: John Granton, MD FRCPC         
Canada, Quebec
Jewish General Hospital Not yet recruiting
Montreal, Quebec, Canada, H3T 1E2
Contact: David Langleben, MD FRCPC    514-340-8222    david.langleben@mcgill.ca   
Principal Investigator: David Langleben, MD FRCPC         
Canada
Institut universitaire de cardiologie et de pneumologie de Québec - Université Laval Not yet recruiting
Quebec, Canada, G1V 4G5
Contact: Steeve Provencher, MD MSc    418-656-4747    Steve.Provencher@criucpq.ulaval.ca   
Principal Investigator: Steeve Provencher, MD MSc         
Sponsors and Collaborators
Northern Therapeutics
Ottawa Hospital Research Institute
  More Information

Responsible Party: Northern Therapeutics
ClinicalTrials.gov Identifier: NCT03001414     History of Changes
Other Study ID Numbers: CT-PAH002
Study First Received: December 15, 2016
Last Updated: December 19, 2016
Individual Participant Data  
Plan to Share IPD: No

Additional relevant MeSH terms:
Hypertension
Hypertension, Pulmonary
Vascular Diseases
Cardiovascular Diseases
Lung Diseases
Respiratory Tract Diseases

ClinicalTrials.gov processed this record on April 24, 2017