Vasotoxicity Surveillance Using EndoPAT: The VASA Pilot Study
试验速览
- 阶段
- 1 期
- 状态
- 招募中
- 发起方
- Mayo Clinic
- 入组人数
- 60
- 试验地点
- 1
- 主要终点
- Change in reactive hyperemia index (RHI)
研究概览
简要总结
This phase I/II trial compares the effect of drugs that causes widening of blood vessels as a result of smooth muscle relaxation (vasodilator therapy) with isosorbide mononitrate, diltiazem or placebo to reduce vasotoxicity in patients with gastrointestinal cancer receiving fluoropyrimidine therapy. Some patients develop chest pain (possibly even a heart attack, a drop in heart function, or a rhythm abnormality) during treatment with a class of cancer drugs known as fluoropyrimidines, which include 5-Fluorouracil (5-FU) and capecitabine. These side effects are believed to be due to the development of an abnormal reactivity of the blood vessels referred to as vasospasm. Vasotoxicity is damage or toxicity inflicted upon blood vessels (vascular system), often causing dysfunction, remodeling, or narrowing (vasoconstriction). It is a broad term used to describe the detrimental effects of certain agents, such as chemotherapy drugs. Researchers want to evaluate how often the reactivity of blood vessels becomes abnormal, during the treatment with 5-FU or capecitabine and how clinically relevant and controllable/preventable this phenomenon is in patients with gastrointestinal cancer.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Sequential
- 主要目的
- Treatment
- 盲法
- Triple (Participant, Investigator, Outcomes Assessor)
盲法说明
In Phase II, patients, treating clinicians, and study staff are blinded to treatment assignment.
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •REGISTRATION: Age ≥ 18 years
- •REGISTRATION: Histologically or cytologically confirmed gastrointestinal malignancy (colon, rectal, gastric, esophageal, or other GI cancer) for which fluoropyrimidine therapy (5-FU or capecitabine) is indicated, either as single agent or in combination with other systemic therapy
- •REGISTRATION: Planned initiation of 5-FU (infusional) or oral capecitabine therapy, either as standard chemotherapy or as a radiosensitizer
- •REGISTRATION: Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0, 1, or 2
- •REGISTRATION: Ability to return to Mayo Clinic for baseline and follow-up EndoPAT testing, electrocardiogram (ECG), Holter monitoring, and blood draws
- •REGISTRATION: Provide written informed consent
- •REGISTRATION: Adequate baseline hemodynamic status: systolic blood pressure ≥ 120 mmHg and resting heart rate ≥ 70 beats/minute (to ensure safety for potential vasodilator therapy in Phase II)
- •RANDOMIZATION: Completed all phase I baseline and follow-up assessments, including EndoPAT, ECG, high-sensitivity cardiac troponin T (hs-TnT), and Holter monitoring
- •RANDOMIZATION: Demonstrated a ≥ 20% decline in reactive hyperemia index (RHI) from baseline at either phase I follow-up assessment as measured by EndoPAT
- •RANDOMIZATION: Adequate hemodynamic status prior to randomization: systolic blood pressure ≥ 120 mmHg and resting heart rate ≥ 70 beats/minute
- •RANDOMIZATION: Ability to tolerate and comply with study medication (isosorbide mononitrate, diltiazem, or placebo) per investigator assessment
- •RANDOMIZATION: Willingness to initiate study medication 5 days before and continue through the assigned fluoropyrimidine treatment cycle
- •RANDOMIZATION: Provide written informed consent for randomization phase
排除标准
- •REGISTRATION: Current or planned treatment with long-acting nitrates or calcium channel blockers at the time of fluoropyrimidine initiation
- •REGISTRATION: Known hypersensitivity or contraindication to nitrates or calcium channel blockers
- •REGISTRATION: Baseline systolic blood pressure < 120 mmHg or resting heart rate < 70 beats/minute
- •REGISTRATION: History of myocardial infarction ≤ 6 months prior to registration, or symptomatic heart failure [decompensated or New York Heart Association (NYHA) III-IV] requiring ongoing therapy
- •REGISTRATION: Recent acute coronary syndrome or coronary revascularization within 3 months of enrollment
- •REGISTRATION: High-grade atrioventricular (AV) block without pacemaker
- •REGISTRATION: Use of PDE-5 inhibitors [e.g. sildenafil (Viagra)] within 48 hours of enrollment
- •REGISTRATION: Uncontrolled intercurrent illness including but not limited to: unstable angina, symptomatic arrhythmias, uncontrolled infection, or psychiatric/social conditions limiting compliance with study requirements
- •REGISTRATION: Physical inability to undergo EndoPAT testing (e.g., digital amputation, severe hand deformity, or other limiting condition)
- •REGISTRATION: Pregnant or nursing persons
- •REGISTRATION: Concurrent enrollment in another interventional clinical trial that, in the opinion of the investigator, would interfere with study endpoints
研究组 & 干预措施
Phase II arm I (Isosorbide mononitrate)
Patients receive isosorbide mononitrate PO QD for 7-12 days on study. Patients also undergo EndoPat, ECG, Holter monitoring for 48 hours, and blood sample collection on study.
干预措施: Isosorbide Mononitrate (Drug)
Phase I (EndoPAT, ECG, Holter monitoring, blood sample)
Patients undergo EndoPat, ECG, Holter monitoring for 48 hours, and blood sample collection during their SOC 5-FU infusion (any time from 2 hours after start to end of infusion) and 12-36 hours post-infusion or SOC capecitabine infusion 5-8 days after starting cycle 1 and 5-8 days after completing cycle 1, before beginning the next cycle of treatment.
干预措施: Capecitabine (Drug)
Phase I (EndoPAT, ECG, Holter monitoring, blood sample)
Patients undergo EndoPat, ECG, Holter monitoring for 48 hours, and blood sample collection during their SOC 5-FU infusion (any time from 2 hours after start to end of infusion) and 12-36 hours post-infusion or SOC capecitabine infusion 5-8 days after starting cycle 1 and 5-8 days after completing cycle 1, before beginning the next cycle of treatment.
干预措施: Fluorouracil (Drug)
Phase I (EndoPAT, ECG, Holter monitoring, blood sample)
Patients undergo EndoPat, ECG, Holter monitoring for 48 hours, and blood sample collection during their SOC 5-FU infusion (any time from 2 hours after start to end of infusion) and 12-36 hours post-infusion or SOC capecitabine infusion 5-8 days after starting cycle 1 and 5-8 days after completing cycle 1, before beginning the next cycle of treatment.
干预措施: Biospecimen Collection (Procedure)
Phase I (EndoPAT, ECG, Holter monitoring, blood sample)
Patients undergo EndoPat, ECG, Holter monitoring for 48 hours, and blood sample collection during their SOC 5-FU infusion (any time from 2 hours after start to end of infusion) and 12-36 hours post-infusion or SOC capecitabine infusion 5-8 days after starting cycle 1 and 5-8 days after completing cycle 1, before beginning the next cycle of treatment.
干预措施: Electrocardiogram (Procedure)
Phase I (EndoPAT, ECG, Holter monitoring, blood sample)
Patients undergo EndoPat, ECG, Holter monitoring for 48 hours, and blood sample collection during their SOC 5-FU infusion (any time from 2 hours after start to end of infusion) and 12-36 hours post-infusion or SOC capecitabine infusion 5-8 days after starting cycle 1 and 5-8 days after completing cycle 1, before beginning the next cycle of treatment.
干预措施: Holter Monitoring (Device)
Phase I (EndoPAT, ECG, Holter monitoring, blood sample)
Patients undergo EndoPat, ECG, Holter monitoring for 48 hours, and blood sample collection during their SOC 5-FU infusion (any time from 2 hours after start to end of infusion) and 12-36 hours post-infusion or SOC capecitabine infusion 5-8 days after starting cycle 1 and 5-8 days after completing cycle 1, before beginning the next cycle of treatment.
干预措施: Medical Device Usage and Evaluation (Other)
Phase I (EndoPAT, ECG, Holter monitoring, blood sample)
Patients undergo EndoPat, ECG, Holter monitoring for 48 hours, and blood sample collection during their SOC 5-FU infusion (any time from 2 hours after start to end of infusion) and 12-36 hours post-infusion or SOC capecitabine infusion 5-8 days after starting cycle 1 and 5-8 days after completing cycle 1, before beginning the next cycle of treatment.
干预措施: Questionnaire Administration (Other)
Phase II arm I (Isosorbide mononitrate)
Patients receive isosorbide mononitrate PO QD for 7-12 days on study. Patients also undergo EndoPat, ECG, Holter monitoring for 48 hours, and blood sample collection on study.
干预措施: Biospecimen Collection (Procedure)
Phase II arm I (Isosorbide mononitrate)
Patients receive isosorbide mononitrate PO QD for 7-12 days on study. Patients also undergo EndoPat, ECG, Holter monitoring for 48 hours, and blood sample collection on study.
干预措施: Electrocardiogram (Procedure)
Phase II arm I (Isosorbide mononitrate)
Patients receive isosorbide mononitrate PO QD for 7-12 days on study. Patients also undergo EndoPat, ECG, Holter monitoring for 48 hours, and blood sample collection on study.
干预措施: Holter Monitoring (Device)
Phase II arm I (Isosorbide mononitrate)
Patients receive isosorbide mononitrate PO QD for 7-12 days on study. Patients also undergo EndoPat, ECG, Holter monitoring for 48 hours, and blood sample collection on study.
干预措施: Medical Device Usage and Evaluation (Other)
Phase II arm I (Isosorbide mononitrate)
Patients receive isosorbide mononitrate PO QD for 7-12 days on study. Patients also undergo EndoPat, ECG, Holter monitoring for 48 hours, and blood sample collection on study.
干预措施: Questionnaire Administration (Other)
Phase II arm II (Diltiazem hydrochloride)
Patients receive diltiazem PO QD for 7-12 days on study. Patients also undergo EndoPat, ECG, Holter monitoring for 48 hours, and blood sample collection on study.
干预措施: Biospecimen Collection (Procedure)
Phase II arm II (Diltiazem hydrochloride)
Patients receive diltiazem PO QD for 7-12 days on study. Patients also undergo EndoPat, ECG, Holter monitoring for 48 hours, and blood sample collection on study.
干预措施: Electrocardiogram (Procedure)
Phase II arm II (Diltiazem hydrochloride)
Patients receive diltiazem PO QD for 7-12 days on study. Patients also undergo EndoPat, ECG, Holter monitoring for 48 hours, and blood sample collection on study.
干预措施: Holter Monitoring (Device)
Phase II arm II (Diltiazem hydrochloride)
Patients receive diltiazem PO QD for 7-12 days on study. Patients also undergo EndoPat, ECG, Holter monitoring for 48 hours, and blood sample collection on study.
干预措施: Medical Device Usage and Evaluation (Other)
Phase II arm II (Diltiazem hydrochloride)
Patients receive diltiazem PO QD for 7-12 days on study. Patients also undergo EndoPat, ECG, Holter monitoring for 48 hours, and blood sample collection on study.
干预措施: Questionnaire Administration (Other)
Phase II arm III (Placebo administration)
Patients receive placebo PO QD for 7-12 days on study. Patients also undergo EndoPat, ECG, Holter monitoring for 48 hours, and blood sample collection on study.
干预措施: Biospecimen Collection (Procedure)
Phase II arm III (Placebo administration)
Patients receive placebo PO QD for 7-12 days on study. Patients also undergo EndoPat, ECG, Holter monitoring for 48 hours, and blood sample collection on study.
干预措施: Electrocardiogram (Procedure)
Phase II arm III (Placebo administration)
Patients receive placebo PO QD for 7-12 days on study. Patients also undergo EndoPat, ECG, Holter monitoring for 48 hours, and blood sample collection on study.
干预措施: Holter Monitoring (Device)
Phase II arm III (Placebo administration)
Patients receive placebo PO QD for 7-12 days on study. Patients also undergo EndoPat, ECG, Holter monitoring for 48 hours, and blood sample collection on study.
干预措施: Medical Device Usage and Evaluation (Other)
Phase II arm III (Placebo administration)
Patients receive placebo PO QD for 7-12 days on study. Patients also undergo EndoPat, ECG, Holter monitoring for 48 hours, and blood sample collection on study.
干预措施: Placebo Administration (Drug)
Phase II arm III (Placebo administration)
Patients receive placebo PO QD for 7-12 days on study. Patients also undergo EndoPat, ECG, Holter monitoring for 48 hours, and blood sample collection on study.
干预措施: Questionnaire Administration (Other)
Phase II arm II (Diltiazem hydrochloride)
Patients receive diltiazem PO QD for 7-12 days on study. Patients also undergo EndoPat, ECG, Holter monitoring for 48 hours, and blood sample collection on study.
干预措施: Diltiazem Hydrochloride (Drug)
结局指标
主要结局
Change in reactive hyperemia index (RHI)
时间窗: Baseline (up to 3 days before start of infusion); during infusion; 12-36 hours post-infusion
Will be analyzed as a continuous variable and paired t-test or Wilcoxon signed-rank test will be used depending on parametric or non-parametric distribution of RHI values. Statistical significance is set at a p-value \< 0.05.
次要结局
- Proportion of patients with RHI decline ≥ 20%(Up to 1 year)
- Proportion of patients with absolute RHI ≤ 2.0(Up to 1 year)
- High-sensitivity troponin T (hsTnT) (indicator of myocardial ischemia)(Up to 1 year)
- Presence of Holter abnormalities (ST-segment changes, arrhythmias)(Up to 1 year)
- Presence of ischemic symptoms (angina or angina equivalents, dyspnea, claudication)(Up to 1 year)
- Seattle Angina Questionnaire (SAQ)(Baseline (up to 3 days before start of infusion); during infusion; 12-36 hours post-infusion)