Epicardial Delivery of XC001 Gene Therapy for Refractory Angina Coronary Treatment (The EXACT Trial): A Phase 1/2 Multi-Center, Open-Label Study to Evaluate Safety, Tolerability and Efficacy

Phase 1

• Conditions: Angina Pectoris Secondary; MedDRA version: 20.0Level: PTClassification code 10002383Term: Angina pectorisSystem Organ Class: 10007541 - Cardiac disorders; Therapeutic area: Diseases [C] - Cardiovascular Diseases [C14]

• Registration Number: EUCTR2021-002803-37-PL
• Lead Sponsor: XyloCor Therapeutics, Inc.

Brief Summary

Not available

Detailed Description

Not available

Study Timeline

• Results First Posted: 1900-01-01
• Study Start: 2021-09-22
• Last Update Posted: 28 March 2022

Recruitment & Eligibility

• Status: ot Recruiting
• Sex: All
• Target Recruitment: 44

Inclusion Criteria

1. Males and females, age 18 to 75 years, inclusive, at the time of signing informed consent form for the 4 dose escalation phase and age 18 to 80 years, inclusive, for the expansion phase at the highest tolerated dose.
2. 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.
3. 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.
4. 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.
5. Two ECG stress tests that adhere to the following (details outlined in the ETT manual):
a. 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;
b. Total exercise duration of 90 seconds to approximately 9 minutes that is limited by angina.
c. 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;
d. 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;
e. 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.)
6. Angina class II - IV as measured by the CCS Functional Classification of Angina Pectoris.
7. 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).
8. 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).
9. Anti-adenovirus serotype 5 neutralizing antibody titer < 1:320.
10. Adequate hematologic function defined as hemoglobin = 10 g/dL, absolute neutrophil count > 1.2 × 103 per µL and platelet count = 75,000 per µL.
11. 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.
12. Adequate renal function defined as the estimated glomerular filtration rate (eGFR) > 60 mL/minute/1.73 m2 by the Modifi

Exclusion Criteria

1. Any of the following:
a. 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;
b. Current hypercholesterolemia defined as low-density lipoprotein (LDL) above 190 mg/dL;
c. 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;
d. 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 (eg 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.
e. Current untreated malignant ventricular arrhythmia;
f. Current untreated bradyarrhythmia for which an artificial pacemaker is indicated;
g. 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);
h. 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); and/or
i. Current mitral or aortic valvular heart disease requiring mechanical intervention.
2. Body mass index that would interfere with any of the protocol-required tests and procedures, including investigational drug administration.
3. 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).
4. 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.
5. Chronic oral corticosteroid therapy or therapy with other immunosuppressive medications.
6. 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).
7. 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.
8. Hypersensitivity to amide-containing agents which are used for control of post-administration pain through an intercostal nerve block.
9. Pregnancy or currently lactating.
10. Receiving an investigational intervention or participating in another clinica

Study & Design

• Study Type: Interventional clinical trial of medicinal product
• Study Design: Not specified

Primary Outcome Measures

Name	Time	Method
Main Objective: To evaluate the safety and tolerability of XC001 through 6 months following a one-time epicardial administration to subjects who have refractory angina.;Secondary Objective: - To evaluate the safety and tolerability of XC001 through 12 months.<br>- To evaluate the effect of XC001 on myocardial ischemia as manifested by exercise tolerance, myocardial perfusion, angina pectoris and physical activity.<br>- To evaluate the effect of XC001 on quality of life (QOL).;Primary end point(s): Safety through Month 6: AEs and SAEs;Timepoint(s) of evaluation of this end point: Safety parameters will be collected at the 6 month visits to assess safety through month 6: AEs and SAEs

Secondary Outcome Measures

Name	Time	Method
Secondary end point(s): - Change from baseline to Month 6 in time to 1 mm ST segment depression during exercise tolerance test (ETT) as assessed by a blinded core laboratory<br>• Change from baseline to Month 6 in total exercise duration during the Modified Bruce protocol ETT<br>• Change from baseline to Month 6 in time to angina during ETT<br>• Change from baseline to Month 6 in Seattle Angina Questionnaire (SAQ) score<br>• Change from baseline to Month 6 in angina class as measured by the Canadian Cardiovascular Society (CCS) Functional Classification of Angina Pectoris<br>• Change from baseline to Month 6 in the frequency of angina episodes, severity of angina episodes and amount of exertion causing angina episode;Timepoint(s) of evaluation of this end point: These will be evaluated at the 6 month visit.