A Trial to Study Neladenoson Bialanate Over 20 Weeks in Patients With Chronic Heart Failure With Preserved Ejection Fraction (PANACHE)

A Multicenter, Randomized, Placebo-controlled, Parallel Group, Double Blind, Dose-finding Phase II Trial to Study the Efficacy, Safety, Pharmacokinetics and Pharmacodynamic Effects of the Oral Partial Adenosine A1 Receptor Agonist Neladenoson Bialanate Over 20 Weeks in Patients With Chronic Heart Failure and Preserved Ejection Fraction

The objective of the study is to find the optimal dose of once daily oral neladenoson bialanate (BAY1067197) when given in addition to appropriate therapy for specific comorbidities.

Study Overview

• Status: Completed
• Conditions: Heart Failure
• Intervention / Treatment: Drug: Neladenoson bialanate (BAY1067197); Drug: Neladenoson bialanate (BAY1067197); Drug: Neladenoson bialanate (BAY1067197); Drug: Neladenoson bialanate (BAY1067197); Drug: Neladenoson bialanate (BAY1067197); Drug: Placebo

• Study Type: Interventional
• Enrollment (Actual): 305
• Phase: Phase 2

Contacts and Locations

Study Locations

• Austria
  • Wien, Austria, 1090
    • Allgemeines Krankenhaus der Stadt Wien
  • Wien, Austria, 1130
    • Krankenhaus Hietzing
  • Niederösterreich
    • St. Pölten, Niederösterreich, Austria, 3100
      • Universitätsklinikum St. Pölten
  • Oberösterreich
    • Braunau, Oberösterreich, Austria, 5280
      • Krankenhaus St. Josef Braunau
    • Linz, Oberösterreich, Austria, 4020
      • Krankenhaus der Elisabethinen Linz GmbH
  • Steiermark
    • Graz, Steiermark, Austria, 8036
      • Medizinische Universität Graz
• Belgium
  • Hasselt, Belgium, 3500
    • Jessa Ziekenhuis
  • Liege, Belgium, 4000
    • CHR de la CITADELLE
  • Roeselare, Belgium, 8800
    • AZ Delta
• Bulgaria
  • Pernik, Bulgaria, 2300
    • Spec Hosp for Active Treatm in Cardiology Sv Georgi Pernik
  • Pleven, Bulgaria, 5800
    • Specialized Hospital for Actrive Treatm of Card - Pleven
  • Sofia, Bulgaria, 1142
    • Medical Center Cardiohelp
  • Sofia, Bulgaria, 1233
    • NMTH Tzar Boris III
  • Sofia, Bulgaria, 1527
    • UMHAT Tsaritsa Joanna-ISUL EAD Sofia
  • Stara Zagora, Bulgaria, 6000
    • MCOMH Preventsia-2000
• Germany
  • Berlin, Germany, 13353
    • Charité Campus Virchow-Klinikum (CVK)
  • Rheinland-Pfalz
    • Mainz, Rheinland-Pfalz, Germany, 55131
      • St. Vincenz und Elisabeth Hospital, Kathol. Klinikum Mainz
  • Sachsen
    • Dresden, Sachsen, Germany, 01069
      • Klinische Forschung Dresden GmbH
  • Thüringen
    • Erfurt, Thüringen, Germany, 99089
      • HELIOS Klinikum Erfurt GmbH
• Greece
  • Athens, Greece, 11527
    • G. GENNIMATAS General State Hospital of Athens
  • Chalkida, Greece, 34100
    • General Hospital of Chalkida
  • Nea Ionia / Athens, Greece, 142 33
    • Konstantopoulio General Hospital of Nea Ionia - AGIA OLGA
  • Thessaloniki, Greece, 54642
    • Hippokration General Hospital of Thessaloniki
  • Voula, Greece, 16673
    • Asklipieion General Hospital of Voulas
  • Attica
    • Kifisia / Athens, Attica, Greece, 14561
      • KAT General Hospital of Athens
• Israel
  • Ashkelon, Israel, 7830604
    • Barzilai Medical Center
  • Hadera, Israel, 3810101
    • Hillel Yaffe Medical Center
  • Haifa, Israel, 3109601
    • Rambam Health Corporation
  • Jerusalem, Israel, 9103102
    • Shaare Zedek Medical Center
  • Jerusalem, Israel
    • Hadassah University Hospital Mount Scopus
  • Tel Aviv, Israel, 6423906
    • Tel-Aviv Sourasky Medical Center
  • Zrifin, Israel, 6093000
    • Assaf Harofeh Medical Center
• Italy
  • Friuli-Venezia Giulia
    • Udine, Friuli-Venezia Giulia, Italy, 33038
      • AAS 3 Friuli Alto Medio Collin
  • Lazio
    • Roma, Lazio, Italy, 00189
      • A.O.U. Sant'Andrea
  • Lombardia
    • Bergamo, Lombardia, Italy, 24127
      • ASST Papa Giovanni XXIII
    • Brescia, Lombardia, Italy, 25123
      • ASST Spedali Civili di Brescia
  • Piemonte
    • Torino, Piemonte, Italy, 10128
      • A.O. Ordine Mauriziano
  • Sardegna
    • Sassari, Sardegna, Italy, 07100
      • A.O.U. di Sassari
  • Toscana
    • Arezzo, Toscana, Italy, 52040
      • AUSL Toscana Sud-Est
• Japan
  • Fukui, Japan, 910-8526
    • Fukui Prefectural Hospital
  • Okayama, Japan, 702-8055
    • Okayama Rosai Hospital
  • Osaka, Japan, 558-8558
    • Osaka General Medical Center
  • Tokushima, Japan, 770-8539
    • Tokushima Prefectural Central Hospital
  • Gifu
    • Seki, Gifu, Japan, 501-3802
      • Chuno Kosei Hospital
  • Hyogo
    • Amagasaki, Hyogo, Japan, 660-8550
      • Hyogo Prefectural Amagasaki General Medical Center
  • Ishikawa
    • Kanazawa, Ishikawa, Japan, 920-8650
      • National Hospital Organization Kanazawa Medical Center
  • Kanagawa
    • Fujisawa, Kanagawa, Japan, 251-0041
      • Shonan Fujisawa Tokushukai Hospital
  • Okinawa
    • Naha, Okinawa, Japan, 902-8511
      • R.I.A.C Naha City Hospital
  • Osaka
    • Kishiwada, Osaka, Japan, 596-8522
      • Kishiwada Tokushukai Hospital
    • Takatsuki, Osaka, Japan, 569-1096
      • Takatsuki Red Cross Hospital
    • Takatsuki, Osaka, Japan, 569-8686
      • Osaka Medical College Hospital
  • Tokyo
    • Hachioji, Tokyo, Japan, 192-0918
      • Minamino Cardiovascular Hospital
    • Shinjuku-ku, Tokyo, Japan, 162-8666
      • Tokyo Women's Medical University Hospital
• Poland
  • Bialystok, Poland, 15-276
    • Uniwersytecki Szpital Kliniczny w Bialymstoku
  • Grodzisk Mazowiecki, Poland, 05-825
    • Szpital Zachodni w Grodzisku Mazowieckim
  • Krakow, Poland, 31-121
    • Szpital Specjalistyczny im. J. Dietla
  • Lodz, Poland, 91-347
    • Wojewodzki Specjalistyczny Szpital im. dr Wl. Bieganskiego
  • Szczecin, Poland, 70-965
    • 109 Szpital Wojskowy z przychodnia SPZOZ
  • Warszawa, Poland, 02-211
    • Szpital Wolski im. dr Anny Gostynskiej SPZOZ
  • Wroclaw, Poland, 50-981
    • IV Wojskowy Szpital Kliniczny z Poliklinika, SPZOZ
• Portugal
  • Coimbra, Portugal, 3000-075
    • CHUC - Hospitais da Universidade de Coimbra
  • Lisboa, Portugal, 1449-005
    • CHLO - Hospital Sao Francisco Xavier
  • Lisboa, Portugal, 1500-650
    • Hospital da Luz
  • Porto, Portugal, 4099-001
    • CHUP, EPE - Hospital de Santo Antonio
• Spain
  • Barcelona, Spain, 08003
    • Hospital del Mar
  • Madrid, Spain, 28007
    • Hospital General Universitario Gregorio Maranon
  • Madrid, Spain, 28040
    • Hospital Clinico Universitario San Carlos
  • Málaga, Spain, 29010
    • Hospital Virgen de la Victoria
  • Valencia, Spain, 46026
    • Hospital Universitari I Politecnic La Fe
  • Valencia, Spain, 46010
    • Hospital Clínico Universitario de Valencia
  • Madrid
    • Aravaca, Madrid, Spain, 28023
      • Hospital Sanitas La Zarzuela
  • Murcia
    • El Palmar, Murcia, Spain, 30120
      • Hospital Universitario "Virgen de la Arrixaca"
• United States
  • Illinois
    • Chicago, Illinois, United States, 60611
      • Northwestern University
  • Missouri
    • Saint Louis, Missouri, United States, 63136
      • St. Louis Heart & Vascular, PC
  • Nebraska
    • Lincoln, Nebraska, United States, 68506
      • BryanLGH Medical Center East
  • North Carolina
    • Winston-Salem, North Carolina, United States, 27157-1045
      • Wake Forest Baptist Health

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 45 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Men or women aged 45 years and older
• Diagnosis of chronic heart failure, NYHA (New York Heart Association) class II-IV, LVEF (left ventricular ejection fraction) ≥ 45% and elevated NT-proBNP

Exclusion Criteria:

• Acute decompensated heart failure within the past 4 weeks
• Inability to exercise
• Previous diagnosis of HFrEF (heart failure with reduced ejection fraction) (LVEF < 40%)

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

6

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Neladenoson bialanate (BAY1067197) (5 mg); Chronic heart failure with preserved ejection fraction	Drug: Neladenoson bialanate (BAY1067197); 5 mg orally once daily for 20 weeks; Drug: Neladenoson bialanate (BAY1067197); 10 mg orally once daily for 20 weeks; Drug: Neladenoson bialanate (BAY1067197); 20 mg orally once daily for 20 weeks; Drug: Neladenoson bialanate (BAY1067197); 30 mg orally once daily for 20 weeks; Drug: Neladenoson bialanate (BAY1067197); 40 mg orally once daily for 20 weeks
Experimental: Neladenoson bialanate (BAY1067197) (10 mg); Chronic heart failure with preserved ejection fraction	Drug: Neladenoson bialanate (BAY1067197); 5 mg orally once daily for 20 weeks; Drug: Neladenoson bialanate (BAY1067197); 10 mg orally once daily for 20 weeks; Drug: Neladenoson bialanate (BAY1067197); 20 mg orally once daily for 20 weeks; Drug: Neladenoson bialanate (BAY1067197); 30 mg orally once daily for 20 weeks; Drug: Neladenoson bialanate (BAY1067197); 40 mg orally once daily for 20 weeks
Experimental: Neladenoson bialanate (BAY1067197) (20 mg); Chronic heart failure with preserved ejection fraction	Drug: Neladenoson bialanate (BAY1067197); 5 mg orally once daily for 20 weeks; Drug: Neladenoson bialanate (BAY1067197); 10 mg orally once daily for 20 weeks; Drug: Neladenoson bialanate (BAY1067197); 20 mg orally once daily for 20 weeks; Drug: Neladenoson bialanate (BAY1067197); 30 mg orally once daily for 20 weeks; Drug: Neladenoson bialanate (BAY1067197); 40 mg orally once daily for 20 weeks
Experimental: Neladenoson bialanate (BAY1067197) (30 mg); Chronic heart failure with preserved ejection fraction	Drug: Neladenoson bialanate (BAY1067197); 5 mg orally once daily for 20 weeks; Drug: Neladenoson bialanate (BAY1067197); 10 mg orally once daily for 20 weeks; Drug: Neladenoson bialanate (BAY1067197); 20 mg orally once daily for 20 weeks; Drug: Neladenoson bialanate (BAY1067197); 30 mg orally once daily for 20 weeks; Drug: Neladenoson bialanate (BAY1067197); 40 mg orally once daily for 20 weeks
Experimental: Neladenoson bialanate (BAY1067197) (40 mg); Chronic heart failure with preserved ejection fraction	Drug: Neladenoson bialanate (BAY1067197); 5 mg orally once daily for 20 weeks; Drug: Neladenoson bialanate (BAY1067197); 10 mg orally once daily for 20 weeks; Drug: Neladenoson bialanate (BAY1067197); 20 mg orally once daily for 20 weeks; Drug: Neladenoson bialanate (BAY1067197); 30 mg orally once daily for 20 weeks; Drug: Neladenoson bialanate (BAY1067197); 40 mg orally once daily for 20 weeks
Placebo Comparator: Placebo; Chronic heart failure with preserved ejection fraction	Drug: Placebo; Orally once daily for 20 weeks

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Absolute Change From Baseline in 6-minute Walking Distance (6MWD) After 20 Weeks of Treatment	The 6MWD test is designed to evaluate a subject's exercise capacity while performing an everyday activity.	Baseline, and up to 20 weeks of treatment

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change From Baseline in Average Weekly Percentage of Maximum Possible Recorded Activity Intensity	AVIVO™ Mobile Patient Management System, a wearable wireless device worn by the subject, was used to monitor subjects' cardiovascular status. The patient's everyday physical activity e.g. duration, intensity, was also tracked by the AVIVO device. For Activity Intensity, the Unit of Measure is "percentage of maximum activity", and length of intervals is "daily".	Baseline, and up to 20 weeks of treatment
Measured Values (Log Transformed) and Absolute Change in NT-proBNP From Baseline to 20 Weeks	NT-proBNP = N-terminal pro-hormone b-type natriuretic peptide	Baseline, and up to 20 weeks of treatment
Measured Values (Log-transformed) and Absolute Change in High Sensitivity Troponin T (Hs-TNT) From Baseline to 20 Weeks	High sensitivity troponin T (hs-TNT) was measured	Baseline, and up to 20 weeks of treatment
Measured Values and Absolute Change in 3 Scores From Kansas City Cardiomyopathy Questionnaire (KCCQ) From Baseline to 20 Weeks: Overall Summary Score, Physical Limitation Score and Total Symptom Score	The KCCQ is the leading health-related quality-of-life measure for patients with chronic heart failure (CHF). It is a 23-item questionnaire that independently measures the impact of patient's heart failure (HF), or its treatment, on 7 distinct domains: 1) Symptom Frequency 2) Symptom Burden 3) Physical Limitation 4) Quality of Life 5) Social Limitations 6) Self-efficacy 7) Symptoms Stability. Overall summary score= mean score of (symptom frequency + symptom burden+ physical limitation + quality of life + social limitation); scores on a scale of 0 to 100, higher scores means better outcome; Physical Limitation: scores on a scale of 0 to 100, higher scores means better outcome; Total symptom score=mean score of (symptom frequency + symptom burden): scores on a scale of 0 to 100, higher scores means better outcome. Positive change means improvement and negative change means deterioration.	Baseline, and up to 20 weeks of treatment

Collaborators and Investigators

• Sponsor: Bayer

Publications and helpful links

General Publications

• Shah SJ, Voors AA, McMurray JJV, Kitzman DW, Viethen T, Bomfim Wirtz A, Huang E, Pap AF, Solomon SD. Effect of Neladenoson Bialanate on Exercise Capacity Among Patients With Heart Failure With Preserved Ejection Fraction: A Randomized Clinical Trial. JAMA. 2019 Jun 4;321(21):2101-2112. doi: 10.1001/jama.2019.6717.

Study record dates

Study Major Dates

• Study Start (Actual): May 10, 2017
• Primary Completion (Actual): May 23, 2018
• Study Completion (Actual): June 20, 2018

Study Registration Dates

• First Submitted: March 15, 2017
• First Submitted That Met QC Criteria: March 28, 2017
• First Posted (Actual): April 4, 2017

Study Record Updates

• Last Update Posted (Actual): July 23, 2019
• Last Update Submitted That Met QC Criteria: July 4, 2019
• Last Verified: July 1, 2019

More Information

Terms related to this study

• Keywords: Chronic Heart Failure; Heart Failure with Preserved Ejection Fraction
• Additional Relevant MeSH Terms: Heart Diseases; Cardiovascular Diseases; Heart Failure
• Other Study ID Numbers: 17582; 2016-004062-26 (EudraCT Number)

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No