Clinical Trial Results:
Controlled trial on the short-term effects of sacubitril/valsartan therapy on cardiac oxygen consumption and efficiency of cardiac work in patients with NYHA II-III heart failure and reduced systolic function using 11C-acetate positron emission tomography and echocardiography
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Summary
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EudraCT number |
2017-002113-64 |
Trial protocol |
FI |
Global end of trial date |
23 Mar 2022
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Results information
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Results version number |
v1(current) |
This version publication date |
05 Apr 2023
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First version publication date |
05 Apr 2023
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Other versions |
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Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
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Trial identification
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Sponsor protocol code |
CLCZ696BFI03
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Additional study identifiers
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ISRCTN number |
- | ||
US NCT number |
NCT03300427 | ||
WHO universal trial number (UTN) |
- | ||
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Sponsors
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Sponsor organisation name |
NovartisPharma AG
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Sponsor organisation address |
Novartis Campus, Basel, Switzerland,
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Public contact |
Study Director , Novartis PharmaAG, 41 613241111, Novartis.email@Novartis.com
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Scientific contact |
Study Director , Novartis PharmaAG, 41 613241111, Novartis.email@Novartis.com
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Paediatric regulatory details
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Is trial part of an agreed paediatric investigation plan (PIP) |
No
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Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Results analysis stage
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Analysis stage |
Final
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Date of interim/final analysis |
23 Mar 2022
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Is this the analysis of the primary completion data? |
No
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Global end of trial reached? |
Yes
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Global end of trial date |
23 Mar 2022
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Was the trial ended prematurely? |
No
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General information about the trial
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Main objective of the trial |
The primary objective of the study was to evaluate the effects of 6 weeks of stable
sacubitril/valsartan therapy, as compared with valsartan therapy, on the efficiency of cardiac
work in patients with New York Heart Association (NYHA) II-III heart failure (HF) and
reduced systolic function using 11C-acetate and echocardiography. In order to do this, the
difference in cardiac efficiency was evaluated by comparing the results obtained after 6 weeks
of stable treatment to the results from the Baseline visit.
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Protection of trial subjects |
The study was in compliance with the ethical principles derived from the Declaration of Helsinki and the International Conference on Harmonization (ICH) Good Clinical Practice (GCP) guidelines. All the local regulatory requirements pertinent to safety of trial subjects were also followed during the conduct of the trial.
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Background therapy |
- | ||
Evidence for comparator |
- | ||
Actual start date of recruitment |
05 Jul 2018
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Long term follow-up planned |
No
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Independent data monitoring committee (IDMC) involvement? |
No
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Population of trial subjects
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Number of subjects enrolled per country |
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Country: Number of subjects enrolled |
Finland: 55
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Worldwide total number of subjects |
55
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EEA total number of subjects |
55
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Number of subjects enrolled per age group |
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In utero |
0
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Preterm newborn - gestational age < 37 wk |
0
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Newborns (0-27 days) |
0
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Infants and toddlers (28 days-23 months) |
0
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Children (2-11 years) |
0
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Adolescents (12-17 years) |
0
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Adults (18-64 years) |
24
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From 65 to 84 years |
31
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85 years and over |
0
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Recruitment
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Recruitment details |
- | |||||||||
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Pre-assignment
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Screening details |
The patients who signed the ICF entered the screening/run-in period of the study. After the screening evaluations and confirmation of eligibility, the patients were allocated randomization numbers and randomized to receive the treatment assigned to each number in a blinded manner. | |||||||||
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Period 1
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Period 1 title |
Overall Study (overall period)
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Is this the baseline period? |
Yes | |||||||||
Allocation method |
Randomised - controlled
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Blinding used |
Double blind | |||||||||
Roles blinded |
Investigator, Carer, Subject, Assessor | |||||||||
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Arms
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Are arms mutually exclusive |
Yes
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Arm title
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sacubitril/valsartan | |||||||||
Arm description |
subjects receive sacubitril/valsartan 100 mg orally twice daily (BID). The dose is then up-titrated to 200 mg BID (or maintained at the starting dose level, if up-titration is not possible). | |||||||||
Arm type |
Experimental | |||||||||
Investigational medicinal product name |
sacubitril/valsartan
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Tablet
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Routes of administration |
Oral use
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Dosage and administration details |
100 mg or 200 mgoral tablet
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Arm title
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valsartan | |||||||||
Arm description |
subjects receive 80 mg orally twice daily (BID). The dose is then up-titrated to 160 mg BID (or maintained at the starting level, if up-titration is not possible) | |||||||||
Arm type |
Active comparator | |||||||||
Investigational medicinal product name |
valsartan
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Tablet
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Routes of administration |
Oral use
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Dosage and administration details |
80 mg or 160 mgoral tablet
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Baseline characteristics reporting groups
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Reporting group title |
sacubitril/valsartan
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Reporting group description |
subjects receive sacubitril/valsartan 100 mg orally twice daily (BID). The dose is then up-titrated to 200 mg BID (or maintained at the starting dose level, if up-titration is not possible). | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
valsartan
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Reporting group description |
subjects receive 80 mg orally twice daily (BID). The dose is then up-titrated to 160 mg BID (or maintained at the starting level, if up-titration is not possible) | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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End points reporting groups
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Reporting group title |
sacubitril/valsartan
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Reporting group description |
subjects receive sacubitril/valsartan 100 mg orally twice daily (BID). The dose is then up-titrated to 200 mg BID (or maintained at the starting dose level, if up-titration is not possible). | ||
Reporting group title |
valsartan
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Reporting group description |
subjects receive 80 mg orally twice daily (BID). The dose is then up-titrated to 160 mg BID (or maintained at the starting level, if up-titration is not possible) | ||
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End point title |
Myocardial energetic efficiency [1] | ||||||||||||||||||
End point description |
Positron emission tomography (PET) imaging and echocardiography were performed before randomization (after a minimum of 4 weeks on stable dose of 80 mg BID or 160 mg BID of valsartan) and repeated after 6 weeks on a stable dose of either 80 mg BID or 160 mg BID of valsartan or 100 mg BID or 200 mg BID of sacubitril/valsartan.
Cardiac efficiency was calculated based on the following formula: Myocardial efficiency = ((SBP x SV x HR)/LV mass)/Kmono
Where
- SBP : Systolic blood pressure during PET
- SV : Stroke volume (Echocardiography)
- HR : Heart rate
- Kmono: Mono-exponential clearance rate (11C-acetate PET- scan)
- LV mass: Left ventricular mass
Visit 3 was performed after the study treatment was on a stable dose for a minimum of 6 weeks. It could be performed before or after 8 weeks, based on when the last dose modification was performed.
No imputation of missing data was performed.
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End point type |
Primary
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End point timeframe |
Baseline, Visit 3 (approximately Week 8)
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| Notes [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: No statistical analysis was planned for this outcome. |
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| No statistical analyses for this end point | |||||||||||||||||||
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End point title |
Change from baseline in myocardial energetic efficiency | ||||||||||||
End point description |
Positron emission tomography (PET) imaging and echocardiography were performed before randomization (after a minimum of 4 weeks on stable dose of 80 mg BID or 160 mg BID of valsartan) and repeated after 6 weeks on a stable dose of either 80 mg BID or 160 mg BID of valsartan or 100 mg BID or 200 mg BID of sacubitril/valsartan.
Cardiac efficiency was calculated based on the following formula: Myocardial efficiency = ((SBP x SV x HR)/LV mass)/Kmono
Where
- SBP : Systolic blood pressure during PET
- SV : Stroke volume (Echocardiography)
- HR : Heart rate
- Kmono: Mono-exponential clearance rate (11C-acetate PET- scan)
- LV mass: Left ventricular mass
Visit 3 was performed after the study treatment was on a stable dose for a minimum of 6 weeks. It could be performed before or after 8 weeks, based on when the last dose modification was performed.
No imputation of missing data was performed.
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End point type |
Primary
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End point timeframe |
Baseline, Visit 3 (approximately Week 8)
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Statistical analysis title |
Myocardial energetic efficiency | ||||||||||||
Statistical analysis description |
Analysis of change from baseline in Myocardial energetic efficiency. The study hypothesis is that short-term therapy with sacubitril/valsartan added on standard HF therapy improves cardiac efficiency in subjects with systolic HF.
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Comparison groups |
sacubitril/valsartan v valsartan
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Number of subjects included in analysis |
55
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Analysis specification |
Pre-specified
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Analysis type |
superiority | ||||||||||||
P-value |
= 0.7594 | ||||||||||||
Method |
ANCOVA | ||||||||||||
Parameter type |
difference in least square means | ||||||||||||
Point estimate |
-900
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Confidence interval |
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level |
95% | ||||||||||||
sides |
2-sided
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lower limit |
-6781.7 | ||||||||||||
upper limit |
4981.8 | ||||||||||||
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End point title |
Viable myocardial energetic efficiency (sensitivity analysis) [2] | ||||||||||||||||||
End point description |
In addition to the derivation of the primary endpoint, an alternative formula was used, where the viable myocardial energetic efficiency was derived as:
Viable myocardial energetic efficiency = ((SBP x SV x HR)/LV mass) / vKmono
Where vKmono is the viable myocardium clearance rate. This alternative parameter was included as a sensitivity analysis to exclude possible bias related to scar tissue in patients with ischemic myopathy.
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End point type |
Primary
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End point timeframe |
Baseline, Visit 3 (approximately Week 8)
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| Notes [2] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: No statistical analysis was planned for this outcome. |
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| No statistical analyses for this end point | |||||||||||||||||||
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End point title |
Change from baseline in viable myocardial energetic efficiency (sensitivity analysis) | ||||||||||||
End point description |
In addition to the derivation of the primary endpoint, an alternative formula was used, where the viable myocardial energetic efficiency was derived as:
Viable myocardial energetic efficiency = ((SBP x SV x HR)/LV mass) / vKmono
Where vKmono is the viable myocardium clearance rate. This alternative parameter was included as a sensitivity analysis to exclude possible bias related to scar tissue in patients with ischemic myopathy.
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End point type |
Primary
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End point timeframe |
Baseline, Visit 3 (approximately Week 8)
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Statistical analysis title |
Viable myocardium energetic efficiency | ||||||||||||
Statistical analysis description |
Analysis of change from baseline in Viable myocardium energetic efficiency. The study hypothesis is that short-term therapy with sacubitril/valsartan added on standard HF therapy improves cardiac efficiency in subjects with systolic HF.
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Comparison groups |
sacubitril/valsartan v valsartan
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Number of subjects included in analysis |
55
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Analysis specification |
Pre-specified
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Analysis type |
superiority | ||||||||||||
P-value |
= 0.8422 | ||||||||||||
Method |
ANCOVA | ||||||||||||
Parameter type |
difference in least square means | ||||||||||||
Point estimate |
-575.5
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Confidence interval |
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level |
95% | ||||||||||||
sides |
2-sided
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lower limit |
-6365.5 | ||||||||||||
upper limit |
5214.5 | ||||||||||||
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Adverse events information
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Timeframe for reporting adverse events |
Adverse events were reported from first dose of study treatment until end of study treatment plus 30 days post treatment, up to a maximum duration of 86 days.
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Adverse event reporting additional description |
The occurrence of adverse events was sought by non-directive questioning of the patient at each visit during the study. Adverse events were also detected when they were volunteered by the patient during or between visits or through physical examination findings, laboratory test findings, or other assessments.
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Assessment type |
Systematic | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Dictionary used for adverse event reporting
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Dictionary name |
MedDRA | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary version |
20.1
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Reporting groups
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Reporting group title |
Valsartan
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Reporting group description |
Valsartan | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Sacubitril/Valsartan
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Reporting group description |
Sacubitril/Valsartan | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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| Frequency threshold for reporting non-serious adverse events: 1% | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Substantial protocol amendments (globally) |
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| Were there any global substantial amendments to the protocol? Yes | |||
Date |
Amendment |
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04 Jan 2019 |
The possibility to perform Screening visit 2 and Visit 2 as remote visits to reduce the number of site visits and thus the burden caused by the study on the patients. |
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24 Jun 2020 |
Changing the upper age limit of the eligible patients from 75 to 80 years to improve of recruitment rate. Several eligible study candidates had been aged between 75 and 80 years. |
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Interruptions (globally) |
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| Were there any global interruptions to the trial? No | |||
Limitations and caveats |
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| Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data. | |||
| None reported | |||
