Ensayos clínicos

Inclusion Criteria:

• Males and females, age 18 to 75 years, inclusive, at the time of signing informed consentform for the 4 dose escalation phase and age 18 to 80 years, inclusive, for the expansion phase at the highest tolerated dose.
• Diagnosis of chronic angina due to obstructive coronary artery disease (CAD) that is refractory to drug therapy and unsuitable for revascularization via coronary artery bypass graft (CABG) or percutaneous coronary intervention (PCI) as confirmed by the ERC.
• History of evidence of reversible left ventricular ischemia, as assessed by stress electrocardiography (ECG including screening), stress echocardiography, single-photon emission computed tomography (SPECT), PET (including screening) or cardiac magnetic resonance (CMR) imaging that has not resolved with intervention or by an acute coronary event.
• Coronary angiography within the past 12 months unless there is a clinical indication from the subject’s medical history or screening tests to warrant a more current procedure as determined by the investigator and/or ERC.
• Two ECG stress tests that adhere to the following (details outlined in the ETT manual):
  • A modified Bruce protocol that includes two three-minute warm-up stages of 1.7mph/0% grade and 1.7mph/5% grade must be used;
  • Total exercise duration of 90 seconds to approximately 9 minutes that is limited by angina;
  • Total exercise duration of the shorter test must be within 25% of the longer test and the difference between the two tests cannot exceed 75 seconds;
  • At least one of the two tests must demonstrate ≥ 1 mm horizontal or down-sloping ST segment depression as compared to baseline, while the other test must demonstrate ≥ 0.5 mm horizontal or down-sloping ST segment depression. This will not be a requirement for subjects in cohorts 1, 2 and 3 while some subjects in cohort 4 and the highest tolerated dose expansion may have to meet this requirement;
  • The tests must be performed at least 72 or more hours apart from each other. A third test is permitted if the second test does not meet the criteria. (NB: The ETT core laboratory must review and approve the ETTs for eligibility).
• Angina class II - IV as measured by the CCS Functional Classification of Angina Pectoris.
• On a stable regimen of anti-anginal, anti-hypertensive, and lipid lowering medications deemed medically appropriate for refractory angina at the discretion of the investigator. The chronic anti-anginal regimen must include at least two functional classes at the maximally tolerated dose for the preceding 30 days prior to the screening visit. Functional classes include beta-blockers, calcium channel blockers, nitrates and metabolic modulators (i.e., ranolazine).
• Formally cleared by the ERC to undergo the gene therapy procedure by a review of past medical history and screening assessments, with emphasis on reversible left ventricular ischemia (further details provided in the ERC Charter).
• Anti-adenovirus serotype 5 neutralizing antibody titer < 1:320.
• Adequate hematologic function defined as hemoglobin ≥ 10 g/dL, absolute neutrophil count > 1.2 × 10^3 per µL and platelet count ≥ 75,000 per µL.
• Adequate hepatic function defined as alanine aminotransferase and aspartate aminotransferase ≤ 3 x ULN and total bilirubin ≤ 2 x ULN unless the subject has a previously known history of Gilbert’s syndrome.
• Adequate renal function defined as the estimated glomerular filtration rate (eGFR) > 60 mL/minute/1.73 m^2 by the Modification of Diet in Renal Disease (MDRD) formula in the 4 dose escalation phase and eGFR > 29 mL/minute/1.73 m^2 in the highest tolerated dose expansion phase, and no current or likely need for hemodialysis in the next 12 months (a retest is permitted if the first test does not meet the criteria and if it meets the inclusion, this test will be used as baseline).
• All male subjects or male partners, regardless of fertility status or the fertility status of their partner, must agree to use a condom and spermicide during any sexual relations for 2 months following administration of investigational product to protect their partner from potential viral shedding.
• All subjects capable of procreation with their partners must agree to use adequate contraception for 2 months following administration of investigational product to avoid pregnancy. Adequate contraception is defined as oral or injectable contraceptives, intrauterine devices, surgical sterilization in addition to/or a combination of a condom and spermicide.
• Agree to not donate sperm or oocytes for 2 months following administration of investigational product.
• Capable of providing informed consent and undergoing all the required tests and procedures in the protocol.

Exclusion Criteria:

• ST elevation myocardial infarction (STEMI) or non-ST elevation myocardial infarction (NSTEMI) not requiring revascularization, transmural myocardial infarction or cerebral vascular accident within the past 30 days prior to the screening visit.
• Current hypercholesterolemia defined as low-density lipoprotein (LDL) above 190 mg/dL;
• Sustained, current systolic blood pressure less than 90 mmHg or uncontrolled hypertension (systolic blood pressure [BP] >180 mmHg, diastolic BP >100 mmHg) despite maximal medical treatment.
• Current electrocardiographic abnormalities that would interfere with ST-segment analysis, such as the presence of a pacemaker, complete Left Bundle Branch Block (LBBB), Left Ventricular Hypertrophy (LVH) with repolarization abnormalities, Wolff-Parkinson-White Syndrome (WPW), or marked resting repolarization abnormalities (e.g., ST segment depression > 1.5 mm). This electrocardiographic requirement may apply to some subjects in dose escalation cohort 4, as well as some subjects in the highest tolerated dose expansion phase but will not be a requirement for subjects in dose escalation cohorts 1, 2 and 3.
• Current untreated malignant ventricular arrhythmia.
• Current untreated bradyarrhythmia for which an artificial pacemaker isindicated.
• Congestive heart failure defined as New York Heart Association Function Class III or IV or left ventricular ejection fraction < 25% within the 6 weeks prior to the screening visit (or as assessed by the screening Echo).
• History of or planned cardiac transplantation (the possibility of an exception can be discussed with the XyloCor medical monitor if the subject is unlikely to undergo a transplant during the duration of the trial due to ranking).
• Current mitral or aortic valvular heart disease requiring mechanical intervention.
• Body mass index that would interfere with any of the protocol-required tests and procedures, including investigational drug administration.
• Diabetic individuals with active proliferative diabetic retinopathy or glycosylated hemoglobin (HbA1c) > 8.5% (a retest is permitted if the first test does not meet the criteria and if it meets the inclusion, this test will be used as baseline).
• A history or evidence of human immunodeficiency virus (HIV) on screening or active hepatitis C virus (HCV), active hepatitis B virus (HBV) or active COVID-19 infection on screening. COVID-19 infection requiring hospitalization (or release from the hospital) within the past 90 days prior to the screening visit.
• Chronic oral corticosteroid therapy or therapy with other immunosuppressive medications.
• Diagnosis of, or treatment for, any cancer within the last 5 years except for basal or squamous cell carcinoma or carcinomas in situ where surgical excision was considered curative. (Past medical history of cancer is not exclusionary as long as the subject has been disease free for at least 5 years since the time of diagnosis and treatment).
• Known hypersensitivity or any other contraindication to adenosine or regadenoson, formulation buffer used to suspend the viral vector or contrast agents used in any of the radiographic procedures or contraindication to general anesthesia.
• Hypersensitivity to amide-containing agents which are used for control of post-administration pain through an intercostal nerve block.
• Pregnancy or currently lactating.
• Receiving an investigational intervention or participating in another clinical trial within 30 days or within 5 half-lives of the drug prior to screening. Exception may be made if the individual is enrolled in a nontherapeutic observational study (registry) or the observational portion of a therapeutic study where the sponsoring authority authorizes enrollment.
• Prior participation in any gene therapy; however, if the study was unblinded or documentation otherwise exists that the subject was randomized to the placebo control group and did not receive active gene transfer agent, the subject may be considered for this study.
• Has a serious or unstable medical or psychological condition (including drug or alcohol abuse) that, in the opinion of the investigator, would compromise the subject’s safety or successful participation in the study or interpretation of study results.