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Design of a Phase 3 trial of intracoronary administration of human adenovirus 5 encoding human adenylyl cyclase type 6 (RT-100) gene transfer in patients with heart failure with reduced left ventricular ejection fraction: The FLOURISH Clinical Trial.
Am Heart J 2018; 201:111-116AH

Abstract

The prognosis of patients with HFrEF remains poor despite the use of current medical and device therapies. Preclinical studies of HFrEF using IC delivery of RT-100, a replication deficient, E1/E3-deleted human adenovirus 5 encoding human AC6 was associated with favorable effects on LV function and remodeling. A recent multicenter, double-blind, placebo-controlled, phase 2 study demonstrated the safety of IC delivery of RT-100 in HFrEF patients and potential efficacy at the higher doses. This phase 2 dose finding study, which included doses not expected to be effective, identified a potential reduction in congestive heart failure admissions in the AC6-treated group one year after randomization. The FLOURISH study is designed to investigate the prospect of reduction of heart failure hospitalization and other clinical adverse events and improvement in EF. The FLOURISH study is a double-blind, placebo-controlled, multicenter Phase 3 clinical trial that will randomize 536 patients to a one-time IC administration of RT-100 (1012 vp) or placebo in a 1:1 ratio. Subjects will be 18-80 years of age, on optimal standard of care HF therapy with LVEF ≥10% and ≤35% by echocardiogram, and will undergo IC administration of RT-100 vs. placebo on Day 1. Follow-up study visits will be performed at Weeks 1 and 4, and Months 3, 6, and 12. Patients will be followed for an additional 36 months for safety assessments with telephone contact at Months 24, 36, and 48. The primary objective is to determine the efficacy of IC RT-100 vs. placebo in reducing the event rate of all (first and repeat) HF hospitalizations occurring from baseline to 12 months. The secondary objectives are to determine the efficacy of IC RT-100 on CV death, all cause death, and all HF events and in improving NYHA functional classification. Exploratory endpoints will include echocardiographic parameters of left ventricular systolic and diastolic function, HF symptoms and physical limitations, 6-minute walking distance, Borg dyspnea score, and NT-proBNP levels. The FLOURISH study, which received fast track designation from the Food and Drug Administration in December 2017, will further investigate the role of a one-time intracoronary injection of RT-100 in reducing HF hospitalizations and will serve as a registration trial (potentially pivotal investigation) for RT-100 as a treatment for HFrEF.

Authors+Show Affiliations

Veterans Affairs San Diego Healthcare System and Department of Medicine, University of California, San Diego, CA. Electronic address: wpenny@ucsd.edu.Cedars Sinai Heart Institute, Los Angeles, CA.Department of Medicine, University of Vermont Medical Center, Burlington, VT.Department of Medicine, University of Miami, Miami, FL.Veterans Affairs San Diego Healthcare System and Department of Medicine, University of California, San Diego, CA.

Pub Type(s)

Journal Article
Review

Language

eng

PubMed ID

29763816

Citation

Penny, William F., et al. "Design of a Phase 3 Trial of Intracoronary Administration of Human Adenovirus 5 Encoding Human Adenylyl Cyclase Type 6 (RT-100) Gene Transfer in Patients With Heart Failure With Reduced Left Ventricular Ejection Fraction: the FLOURISH Clinical Trial." American Heart Journal, vol. 201, 2018, pp. 111-116.
Penny WF, Henry TD, Watkins MW, et al. Design of a Phase 3 trial of intracoronary administration of human adenovirus 5 encoding human adenylyl cyclase type 6 (RT-100) gene transfer in patients with heart failure with reduced left ventricular ejection fraction: The FLOURISH Clinical Trial. Am Heart J. 2018;201:111-116.
Penny, W. F., Henry, T. D., Watkins, M. W., Patel, A. N., & Hammond, H. K. (2018). Design of a Phase 3 trial of intracoronary administration of human adenovirus 5 encoding human adenylyl cyclase type 6 (RT-100) gene transfer in patients with heart failure with reduced left ventricular ejection fraction: The FLOURISH Clinical Trial. American Heart Journal, 201, pp. 111-116. doi:10.1016/j.ahj.2018.04.005.
Penny WF, et al. Design of a Phase 3 Trial of Intracoronary Administration of Human Adenovirus 5 Encoding Human Adenylyl Cyclase Type 6 (RT-100) Gene Transfer in Patients With Heart Failure With Reduced Left Ventricular Ejection Fraction: the FLOURISH Clinical Trial. Am Heart J. 2018;201:111-116. PubMed PMID: 29763816.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Design of a Phase 3 trial of intracoronary administration of human adenovirus 5 encoding human adenylyl cyclase type 6 (RT-100) gene transfer in patients with heart failure with reduced left ventricular ejection fraction: The FLOURISH Clinical Trial. AU - Penny,William F, AU - Henry,Timothy D, AU - Watkins,Matthew W, AU - Patel,Amit N, AU - Hammond,H Kirk, Y1 - 2018/04/06/ PY - 2017/11/16/received PY - 2018/04/02/accepted PY - 2018/5/16/pubmed PY - 2019/4/19/medline PY - 2018/5/16/entrez SP - 111 EP - 116 JF - American heart journal JO - Am. Heart J. VL - 201 N2 - The prognosis of patients with HFrEF remains poor despite the use of current medical and device therapies. Preclinical studies of HFrEF using IC delivery of RT-100, a replication deficient, E1/E3-deleted human adenovirus 5 encoding human AC6 was associated with favorable effects on LV function and remodeling. A recent multicenter, double-blind, placebo-controlled, phase 2 study demonstrated the safety of IC delivery of RT-100 in HFrEF patients and potential efficacy at the higher doses. This phase 2 dose finding study, which included doses not expected to be effective, identified a potential reduction in congestive heart failure admissions in the AC6-treated group one year after randomization. The FLOURISH study is designed to investigate the prospect of reduction of heart failure hospitalization and other clinical adverse events and improvement in EF. The FLOURISH study is a double-blind, placebo-controlled, multicenter Phase 3 clinical trial that will randomize 536 patients to a one-time IC administration of RT-100 (1012 vp) or placebo in a 1:1 ratio. Subjects will be 18-80 years of age, on optimal standard of care HF therapy with LVEF ≥10% and ≤35% by echocardiogram, and will undergo IC administration of RT-100 vs. placebo on Day 1. Follow-up study visits will be performed at Weeks 1 and 4, and Months 3, 6, and 12. Patients will be followed for an additional 36 months for safety assessments with telephone contact at Months 24, 36, and 48. The primary objective is to determine the efficacy of IC RT-100 vs. placebo in reducing the event rate of all (first and repeat) HF hospitalizations occurring from baseline to 12 months. The secondary objectives are to determine the efficacy of IC RT-100 on CV death, all cause death, and all HF events and in improving NYHA functional classification. Exploratory endpoints will include echocardiographic parameters of left ventricular systolic and diastolic function, HF symptoms and physical limitations, 6-minute walking distance, Borg dyspnea score, and NT-proBNP levels. The FLOURISH study, which received fast track designation from the Food and Drug Administration in December 2017, will further investigate the role of a one-time intracoronary injection of RT-100 in reducing HF hospitalizations and will serve as a registration trial (potentially pivotal investigation) for RT-100 as a treatment for HFrEF. SN - 1097-6744 UR - https://www.unboundmedicine.com/medline/citation/29763816/Design_of_a_Phase_3_trial_of_intracoronary_administration_of_human_adenovirus_5_encoding_human_adenylyl_cyclase_type_6__RT_100__gene_transfer_in_patients_with_heart_failure_with_reduced_left_ventricular_ejection_fraction:_The_FLOURISH_Clinical_Trial_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0002-8703(18)30112-1 DB - PRIME DP - Unbound Medicine ER -