Clinical trial NCT03039751: Adenovirus Vascular Endothelial Growth Factor D (AdvVEGF-D) Therapy for Treatment of Refractory Angina Pectoris
Official title: Clinical Development and Proof of Principle Testing of New Regenerative Adenovirus Vascular Endothelial Growth Factor (VEGF-D) Therapy for Cost-effective Treatment of Refractory Angina. A Phase II Randomized, Double-blinded, Placebo-controlled Study (ReGenHeart)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Refractory Angina Pectoris
Gene Transfer
Coronary Artery Disease
Lead sponsor: Kuopio University Hospital
Sponsor class: OTHER
Collaborators: name: Queen Mary University of London
name: University College, London
name: Medical University of Vienna
name: Servicio Madrileño de Salud, Madrid, Spain
name: FinVector Vision Therapies Oy
name: Śląski Uniwersytet Medyczny w Katowicach
name: Rigshospitalet, Denmark
name: Euram Limited
First posted: 2017-02-01
Enrollment: 63
Sex: ALL
Minimum age (years): 30
Maximum age (years): 85
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: The purpose of the study is to evaluate the safety and efficacy of catheter mediated endocardial adenovirus-mediated vascular endothelial growth factor-D (AdVEGF-D) regenerative gene transfer in patients with refractory angina to whom revascularisation cannot be performed.

Detailed description: Study overview:

The purpose of the study is to evaluate the safety and efficacy of catheter mediated AdVEGF-D regenerative gene transfer in patients with refractory angina to whom revascularisation cannot be performed.

Primary objectives:

To test the efficacy of the therapy to improve functional capacity using 6 minute walking test after 6 months follow-up and improvement of symptoms assessed by Canadian Cardiovascular Society (CCS) class.

Secondary objectives:

Efficacy of the gene transfer to increase to improve functional capacity using 6 minute walking test and improvement of symptoms assessed by CCS class after 12 months as well as increase in myocardial perfusion assessed 6 months after the gene transfer. In addition, at 6 and 12 months timepoints, the improvement quality of life (QoL), the use of angina pectoris medication, major adverse cardiac events related to coronary artery disease (cardiovascular death, myocardial infarction, stroke, revascularization and hospital admission due to coronary artery disease) or a combined endpoint of the above (Major Adverse Cardiac Events, MACE) will be evaluated.

Study design:

ReGenHeart is a randomized, double-blinded, placebo-controlled multicentre phase II study which will be conducted at 6 centers. The study will evaluate the efficacy and safety of catheter mediated endocardial AdVEGF-D regenerative gene transfer in 180 patients with angina pectoris or equivalent symptom despite optimal medical therapy and who are not suitable candidates for coronary revascularization with coronary artery bypass grafting (CABG) or percutaneous coronary intervention (PCI) (refractory angina patients).

Study population:

180 patients will be recruited from the six centers in 2 years. The patients will be selected for the trial on the basis of medical history, general status, laboratory analyses, coronary angiogram and 6-minute walking test. Patients with CCS 2-3 angina pectoris despite optimal medical therapy and who are not eligible for coronary angioplasty or bypass operation due to diffuse coronary stenosis, small coronary vessels, repeated revascularization or too high risk for operation, will be included.

The number of subjects to be recruited and randomized to the trial will be 180 (2:1 ratio to the treatment and control groups).

Investigational drug product:

First generation replication-deficient AdVEGF-D produced in 293 cells will be injected into ten sites in the endocardium. The dose of 1x1011 vp in a total volume of 2 ml (10 times 0.2 ml) will be used. Control patients will be treated and operated exactly in the same way except that placebo (buffer solution without gene) injection into the myocardium is used.

Eligibility criteria: Inclusion Criteria:

* informed consent signed
* age \> 30 but \< 85 years
* significant angina pectoris (CCS 2-3) despite of optimal medication
* significant stenosis (\> 60%) in coronary angiography (\< 6 months)
* contraindication to CABG or PCI due to diffuse or distal stenosis, chronic total occlusion, vessels with difficult anatomy, stenosis with severe calcifications and stenosis in small vessels (\<2.5 mm))
* angina pectoris or equivalent symptoms in the 6-minute walking exercise test
* left ventricle wall \> 8 mm detected by transthoracic echocardiography or magnetic resonance imaging (treatment area)

Exclusion Criteria:

* women in fertile age
* diabetes mellitus with severe complications such as diabetic retinopathy or nephropathy
* clinically significant anemia (hemoglobin count \< 120 mg/l in male, \< 110 mg/l in female; hematocrit \< 0.36), leukopenia (b-leukocyte count \< 3.0x109/l), leukocytosis (b-leukocyte count \> 12.0x109/l) or thrombocytopenia (b-thrombocyte count \< 100x109/l)
* renal insufficiency (P-creatinine \> 160 mg/l)
* liver insufficiency (P-alanine aminotransferase or P-alkaline phosphatase over 2 x normal)
* haematuria of unknown origin
* severe hypertension (systolic blood pressure \> 200 mmHg or diastolic blood pressure \> 110 mmHg) or significant hypotension (systolic blood pressure \< 90 mmHg)
* significant obesity (Body Mass Index \> 35)
* acute infection
* immunosuppressive medication
* significant impairment of left ventricular function (ejection fraction \< 25% in echocardiography)
* symptomatic congestive heart failure (New York Heart Association class 3-4)
* haemodynamically significant (grade 3-4/4) aortic or mitral regurgitation or other heart disease needing surgery
* recent (\< 6 weeks) acute coronary syndrome or myocardial infarction, PCI or CABG, stroke or transient ischemic attack (TIA)
* current or suspected malignancy

Primary outcomes:
measure: Functional capacity at 6 months
timeFrame: 6 months after gene transfer
measure: Severity of angina pectoris symptoms at 6 months
timeFrame: 6 months after gene transfer
Secondary outcomes:
measure: Functional capacity at 12 months
timeFrame: 12 months after gene transfer
measure: Severity of angina pectoris symptoms at 12 months
timeFrame: Time Frame: 12 months after gene transfer
measure: Myocardial perfusion at 6 months
timeFrame: 6 months after gene transfer
measure: Quality of Life (EQ-5) at 6 and 12 months
timeFrame: 6 and 12 months after gene transfer
measure: Quality of Life (Short-Form Health Survey) at 6 and 12 months
timeFrame: 6 and 12 months after gene transfer
measure: Quality of Life (Seattle Angina Questionnaire ) at 6 and 12 months
timeFrame: 6 and 12 months after gene transfer
measure: Angina pectoris medication at 6 and 12 months
timeFrame: 6 and 12 months after gene transfer
measure: Adverse cardiac events at 6 and 12 months
timeFrame: 6 and 12 months after gene transfer
Other outcomes:
Locations:
city: Copenhagen
country: Denmark
facility: Rigshospitalet
city: Kuopio
country: Finland
facility: Kuopio University Hospital
Study officials:
affiliation: Kuopio University Hospital
name: Seppo Ylä-Herttuala
role: STUDY_DIRECTOR
References: