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出境医 / 临床实验 / Beta 3 Agonist Treatment in Heart Failure-2 (BEAT-HF II)

Beta 3 Agonist Treatment in Heart Failure-2 (BEAT-HF II)

Study Description
Brief Summary:

Objective: The objective of the study is to assess the structural and functional cardiac effects of treatment with the beta 3 AR agonist Mirabegron in patients with moderate to severe chronic heart failure (LVEF<35%, NYHA III-IV).

The study is a randomized, placebo-controlled, double-blinded trial in two phases with two hypotheses:

Chronic study - study A: Long-term treatment (3 months) with the β3 adrenergic receptor agonist Mirabegron is beneficial in patients with moderate to severe human heart failure

Invasive study - Study B: Administration of Mirabegron in patients with heart failure leads to an immediate increase in cardiac output at a constant or reduced left ventricular filling pressure during submaximal exercise

Specific aims

  1. Determine safety of administration of Mirabegron to patients with moderate to severe heart failure.
  2. Determine if treatment with Mirabegron for 3 months induces beneficial cardiac structural remodelling in patients with moderate to severe heart failure. In an open-label follow-up to determine the effects of Mirabegron after an extended duration (a total of 12 months).
  3. Determine if Mirabegron improves symptoms and exercise capacity as indicated by questionnaires and 6 min walk test in patients with moderate to severe heart failure.
  4. Determine effects of Mirabegron on cardiac conduction, repolarisation and rhythms and arrhythmias in patients with moderate to severe heart failure.
  5. Determine effects of Mirabegron on circulating biomarkers in patients with moderate to severe heart failure.
  6. Determine the immediate and short term haemodynamic effects of Mirabron as measured by CT and invasively.

Condition or disease Intervention/treatment Phase
Heart Failure With Reduced Ejection Fraction NYHA Class III-IV Drug: Mirabegron Phase 2 Phase 3

Study Design
Layout table for study information
Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 56 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: Beta 3 Agonist Treatment in Heart Failure-2
Actual Study Start Date : January 23, 2017
Estimated Primary Completion Date : December 1, 2020
Estimated Study Completion Date : December 1, 2020
Arms and Interventions
Arm Intervention/treatment
Active Comparator: Mirabegron
Active treatment arm (mirabegron)
 Drug: Mirabegron

Study A The maximum tolerated dose up to a maximum of 300 mg per day for 26 weeks.

Study B One single dose of 300 mg at day one followed by 150 mg x 2 for 1 week (8-11 days).

Other Name: Placebo
Placebo Comparator: Placebo
Placebo
 Drug: Mirabegron

Study A The maximum tolerated dose up to a maximum of 300 mg per day for 26 weeks.

Study B One single dose of 300 mg at day one followed by 150 mg x 2 for 1 week (8-11 days).

Other Name: Placebo
Outcome Measures
Primary Outcome Measures :
  1. Increase in left ventricular ejection fraction as measured by computed tomography [ Time Frame: 3 months ]
    Study A

  2. Change in invasive hemodynamics assesses by right heart catherization [ Time Frame: At 3 hours and at 1 week ]
    Study B is explorative assessing the effect on invasive parameters including cardiac output, pulmonary wedge pressure and pulmonary and systemic vascular resistance.


Eligibility Criteria
Layout table for eligibility information
Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. Stable heart failure NYHA class III-IV on ischemic or non-ischemic basis
  2. Left ventricular ejection fraction (LVEF) < 35% as assessed by cardiac CT
  3. NT proBNP > 1000 pg/ml
  4. On optimised evidence-based pharmacological HF treatment stable ≥2 weeks with no current plan for changing HF therapy. The therapy must include a beta-blocker.
  5. No change in diuretics ≤1 week
  6. No admittances to hospital for treatment with intravenously administered positive inotropic agents ≤ 4 weeks.
  7. >18 years

Exclusion Criteria:

  1. Acute myocardial infarction (AMI) or revascularisation < 3 month ago
  2. Uncorrected significant primary obstructive valve disease
  3. Planned major surgery including cardiac revascularisation
  4. Hemodynamically significant obstructive cardiomyopathy
  5. Acute myocarditis or constrictive pericarditis
  6. Clinically significant hepatic (transaminases or bilirubin x 3 above upper reference level) or renal (GFR< 30 ml/min/1,73 m2) diseases
  7. Heart failure due to uncorrected thyroid disease
  8. Cardiac mechanical support
  9. < 6 months after CRT
  10. Uncontrolled hypotension (defined as symptomatic systolic blood pressure < 80 mmHg) - or hypertension (defined as systolic at 180 mmHg or above and/or diastolic blood pressure at 110 mmHg or below)
  11. Unable to give informed consent
  12. Reduced compliance
  13. All women of child bearing potential will be required to use adequate contraception
  14. Pregnant or lactating women
  15. Treatment with a tricyclic antidepressant or CYP2D6 substrates other than beta-blockers or treatment with digoxin.
  16. Known allergy to iodine containing contrast
  17. Estimated GFR < 30 ml/min/1.73 m2
  18. Congenital or drug induced QT prolongation
Contacts and Locations

Locations
Layout table for location information
Denmark
Rigshospitalet
Copenhagen, Denmark, 2100
Sponsors and Collaborators
Henning Bundgaard
Bispebjerg-Frederiksberg Hospital, Denmark
Hillerød hospital, Denmark
Herlev Hospital
Hvidovre University Hospital
Bornholm Hospital, Denmark
Royal North Shore Hospital
Tracking Information
First Submitted Date  ICMJE July 4, 2017
First Posted Date  ICMJE April 24, 2019
Last Update Posted Date October 19, 2020
Actual Study Start Date  ICMJE January 23, 2017
Estimated Primary Completion Date December 1, 2020   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: April 23, 2019)
  • Increase in left ventricular ejection fraction as measured by computed tomography [ Time Frame: 3 months ]
    Study A
  • Change in invasive hemodynamics assesses by right heart catherization [ Time Frame: At 3 hours and at 1 week ]
    Study B is explorative assessing the effect on invasive parameters including cardiac output, pulmonary wedge pressure and pulmonary and systemic vascular resistance.
Original Primary Outcome Measures  ICMJE Same as current
Change History
Current Secondary Outcome Measures  ICMJE Not Provided
Original Secondary Outcome Measures  ICMJE Not Provided
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Beta 3 Agonist Treatment in Heart Failure-2
Official Title  ICMJE Beta 3 Agonist Treatment in Heart Failure-2
Brief Summary

Objective: The objective of the study is to assess the structural and functional cardiac effects of treatment with the beta 3 AR agonist Mirabegron in patients with moderate to severe chronic heart failure (LVEF<35%, NYHA III-IV).

The study is a randomized, placebo-controlled, double-blinded trial in two phases with two hypotheses:

Chronic study - study A: Long-term treatment (3 months) with the β3 adrenergic receptor agonist Mirabegron is beneficial in patients with moderate to severe human heart failure

Invasive study - Study B: Administration of Mirabegron in patients with heart failure leads to an immediate increase in cardiac output at a constant or reduced left ventricular filling pressure during submaximal exercise

Specific aims

  1. Determine safety of administration of Mirabegron to patients with moderate to severe heart failure.
  2. Determine if treatment with Mirabegron for 3 months induces beneficial cardiac structural remodelling in patients with moderate to severe heart failure. In an open-label follow-up to determine the effects of Mirabegron after an extended duration (a total of 12 months).
  3. Determine if Mirabegron improves symptoms and exercise capacity as indicated by questionnaires and 6 min walk test in patients with moderate to severe heart failure.
  4. Determine effects of Mirabegron on cardiac conduction, repolarisation and rhythms and arrhythmias in patients with moderate to severe heart failure.
  5. Determine effects of Mirabegron on circulating biomarkers in patients with moderate to severe heart failure.
  6. Determine the immediate and short term haemodynamic effects of Mirabron as measured by CT and invasively.
Detailed Description Not Provided
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Phase 3
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Condition  ICMJE Heart Failure With Reduced Ejection Fraction NYHA Class III-IV
Intervention  ICMJE Drug: Mirabegron

Study A The maximum tolerated dose up to a maximum of 300 mg per day for 26 weeks.

Study B One single dose of 300 mg at day one followed by 150 mg x 2 for 1 week (8-11 days).

Other Name: Placebo
Study Arms  ICMJE
  • Active Comparator: Mirabegron
    Active treatment arm (mirabegron)
    Intervention: Drug: Mirabegron
  • Placebo Comparator: Placebo
    Placebo
    Intervention: Drug: Mirabegron
Publications * Bundgaard H, Axelsson A, Hartvig Thomsen J, Sørgaard M, Kofoed KF, Hasselbalch R, Fry NA, Valeur N, Boesgaard S, Gustafsson F, Køber L, Iversen K, Rasmussen HH. The first-in-man randomized trial of a beta3 adrenoceptor agonist in chronic heart failure: the BEAT-HF trial. Eur J Heart Fail. 2017 Apr;19(4):566-575. doi: 10.1002/ejhf.714. Epub 2016 Dec 18.

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Enrolling by invitation
Estimated Enrollment  ICMJE
 (submitted: April 23, 2019) 		56
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE December 1, 2020
Estimated Primary Completion Date December 1, 2020   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  1. Stable heart failure NYHA class III-IV on ischemic or non-ischemic basis
  2. Left ventricular ejection fraction (LVEF) < 35% as assessed by cardiac CT
  3. NT proBNP > 1000 pg/ml
  4. On optimised evidence-based pharmacological HF treatment stable ≥2 weeks with no current plan for changing HF therapy. The therapy must include a beta-blocker.
  5. No change in diuretics ≤1 week
  6. No admittances to hospital for treatment with intravenously administered positive inotropic agents ≤ 4 weeks.
  7. >18 years

Exclusion Criteria:

  1. Acute myocardial infarction (AMI) or revascularisation < 3 month ago
  2. Uncorrected significant primary obstructive valve disease
  3. Planned major surgery including cardiac revascularisation
  4. Hemodynamically significant obstructive cardiomyopathy
  5. Acute myocarditis or constrictive pericarditis
  6. Clinically significant hepatic (transaminases or bilirubin x 3 above upper reference level) or renal (GFR< 30 ml/min/1,73 m2) diseases
  7. Heart failure due to uncorrected thyroid disease
  8. Cardiac mechanical support
  9. < 6 months after CRT
  10. Uncontrolled hypotension (defined as symptomatic systolic blood pressure < 80 mmHg) - or hypertension (defined as systolic at 180 mmHg or above and/or diastolic blood pressure at 110 mmHg or below)
  11. Unable to give informed consent
  12. Reduced compliance
  13. All women of child bearing potential will be required to use adequate contraception
  14. Pregnant or lactating women
  15. Treatment with a tricyclic antidepressant or CYP2D6 substrates other than beta-blockers or treatment with digoxin.
  16. Known allergy to iodine containing contrast
  17. Estimated GFR < 30 ml/min/1.73 m2
  18. Congenital or drug induced QT prolongation
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE Denmark
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT03926754
Other Study ID Numbers  ICMJE 2016-002367-34
H-16030780 ( Other Identifier: Regional Ethics Committee )
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: No
IPD Sharing Statement  ICMJE
Plan to Share IPD: Undecided
Responsible Party Henning Bundgaard, Rigshospitalet, Denmark
Study Sponsor  ICMJE Henning Bundgaard
Collaborators  ICMJE
  • Bispebjerg-Frederiksberg Hospital, Denmark
  • Hillerød hospital, Denmark
  • Herlev Hospital
  • Hvidovre University Hospital
  • Bornholm Hospital, Denmark
  • Royal North Shore Hospital
Investigators  ICMJE Not Provided
PRS Account Rigshospitalet, Denmark
Verification Date October 2020

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP

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