Clinical Trial Results:
β3 adrenergic agoniSt treatment in chronic Pulmonary HypERtEnsion secondary to heart failure: a randomized placebo-controlled phase 2 clinical trial
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Summary
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EudraCT number |
2016-002949-32 |
Trial protocol |
ES |
Global end of trial date |
04 Jun 2021
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Results information
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Results version number |
v1(current) |
This version publication date |
29 Dec 2022
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First version publication date |
29 Dec 2022
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Other versions |
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Summary report(s) |
Sphere_End of Study EMA |
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 |
SPHERE-HF
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Additional study identifiers
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ISRCTN number |
- | ||
US NCT number |
NCT02775539 | ||
WHO universal trial number (UTN) |
- | ||
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Sponsors
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Sponsor organisation name |
Fundació Clínic per la Recerca Biomédica
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Sponsor organisation address |
c/ Villarroel, 170, Barcelona, Spain, 08036
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Public contact |
Dra. Ana García Álvarez, Fundació Clínic per la Recerca Biomédica, 34 9322754004031, ANAGARCI@clinic.cat
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Scientific contact |
Dra. Ana García Álvarez, Fundació Clínic per la Recerca Biomédica, 34 9322754004031, ANAGARCI@clinic.cat
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Sponsor organisation name |
CNIC
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Sponsor organisation address |
c/ Melchor Fernández Almagro 3, Madrid, Spain, 28029
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Public contact |
Ana Gracía Álvarez, CNIC, 34 9145312001507, ana.garcia@cnic.es
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Scientific contact |
Ana Gracía Álvarez, CNIC, 34 9145312001507, ana.garcia@cnic.es
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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 |
31 Oct 2022
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Is this the analysis of the primary completion data? |
Yes
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Primary completion date |
04 Jun 2021
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Global end of trial reached? |
Yes
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Global end of trial date |
04 Jun 2021
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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 overall objective is to evaluate the efficacy and safety of mirabegron for the treatment of patients with PH secondary to HF. The primary objective is changes in PVR after 16 weeks of treatment.
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Protection of trial subjects |
Due to the characteristics of the study has not been used specific measurements.
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Background therapy |
- | ||
Evidence for comparator |
The specific control chosen was placebo concurrent control (as there is no treatment approved for this indication). The excipient for placebo capsules (mixture of microcrystalline cellulose and colloidal silica) was received from the manufacturer (Fagron Iberica S.A.U, Terrassa, Spain) and included in capsules. | ||
Actual start date of recruitment |
09 Jan 2017
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Long term follow-up planned |
No
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Independent data monitoring committee (IDMC) involvement? |
Yes
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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 |
Spain: 80
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Worldwide total number of subjects |
80
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EEA total number of subjects |
80
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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) |
28
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From 65 to 84 years |
52
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85 years and over |
0
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Recruitment
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Recruitment details |
The study was conducted in Spain at five sites of Barcelona and Madrid, and was start on 21 June 2017 with the first patient enrolled. The recruitment was for 2 years with a follow-up of 5 months. The last patient completed (end of study) was on 4 June 2021. | ||||||||||||||||||
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Pre-assignment
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Screening details |
Patients with PH associated with HF were screened. Eligible participants were adults aged 18 or over with symptomatic HF (NYHA functional class II-III) and secondary CpcPH who were on optimized evidence-based pharmacological treatment and stable clinical condition during the 30 days preceding recruitment. | ||||||||||||||||||
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Period 1
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Period 1 title |
Overall Trial (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 |
Subject, Investigator, Monitor | ||||||||||||||||||
Blinding implementation details |
Labeled was done in a blinded manner to guarantee masking of patients and physicians. The randomization list was provided exclusively to the pharmacy department, which was responsible for the preparation of medication kits by identifying them with a unique sequential number for
the entire study and provide them to the centers. Researchers assigned medication kits in a sequential order and recorded the kit number provided to each patient in the data collection system.
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Arms
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Are arms mutually exclusive |
No
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Arm title
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Mirabregon | ||||||||||||||||||
Arm description |
- | ||||||||||||||||||
Arm type |
Experimental | ||||||||||||||||||
Investigational medicinal product name |
Mirabegron
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Investigational medicinal product code |
YM178
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Other name |
Betmiga
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Pharmaceutical forms |
Tablet
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Routes of administration |
Oral use
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Dosage and administration details |
Mirabegron: 50 mg daily, titrated till 200 mg daily for 16 weeks.
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Arm title
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Placebo | ||||||||||||||||||
Arm description |
- | ||||||||||||||||||
Arm type |
Placebo | ||||||||||||||||||
Investigational medicinal product name |
Placebo
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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 |
Placebo: 50 mg daily, titrated till 200 mg daily, for 16 weeks. The excipient for placebo capsules (mixture of microcrystalline cellulose and
colloidal silica) was received from the manufacturer (Fagron Iberica S.A.U, Terrassa, Spain) and included in capsules.
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Baseline characteristics reporting groups
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Reporting group title |
Mirabregon
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Reporting group description |
- | ||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Placebo
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Reporting group description |
- | ||||||||||||||||||||||||||||||||||||||||
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Subject analysis sets
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Subject analysis set title |
Final analysis
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Subject analysis set type |
Full analysis | ||||||||||||||||||||||||||||||||||||||||
Subject analysis set description |
Of the 151 patients screened from June 2017 to December 2020, 81 were initially considered eligible for randomization. One patient was excluded after randomization because a lung ventilation-perfusion scan revealed a segmental perfusion defect raising doubts about the potential thromboembolic origin of PH. Of the 80 patients who were included in the ITT population, 67 underwent a second right heart catheterization at 16 weeks and all of them but one achieved at least 80% of therapeutic compliance, so these 66 patients composed the PP population (30 allocated to mirabegron and 36 to placebo). Reasons for withdrawal was ineligible for the study.
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End points reporting groups
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Reporting group title |
Mirabregon
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Reporting group description |
- | ||
Reporting group title |
Placebo
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Reporting group description |
- | ||
Subject analysis set title |
Final analysis
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Subject analysis set type |
Full analysis | ||
Subject analysis set description |
Of the 151 patients screened from June 2017 to December 2020, 81 were initially considered eligible for randomization. One patient was excluded after randomization because a lung ventilation-perfusion scan revealed a segmental perfusion defect raising doubts about the potential thromboembolic origin of PH. Of the 80 patients who were included in the ITT population, 67 underwent a second right heart catheterization at 16 weeks and all of them but one achieved at least 80% of therapeutic compliance, so these 66 patients composed the PP population (30 allocated to mirabegron and 36 to placebo). Reasons for withdrawal was ineligible for the study.
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End point title |
PVR by RHC | |||||||||
End point description |
Primary outcome will be the change from baseline to week 16 in PVR by RHC. PVR will be calculated in Wood units as: (mean PAP [in mmHg] – PAWP [in mmHg])/cardiac output (L/min).
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End point type |
Primary
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End point timeframe |
After 16 weeks of treatment.
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Statistical analysis title |
Statistical and analytical plans | |||||||||
Comparison groups |
Mirabregon v Placebo
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Number of subjects included in analysis |
80
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Analysis specification |
Pre-specified
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Analysis type |
other [1] | |||||||||
P-value |
> 0.1 | |||||||||
Method |
ANCOVA | |||||||||
Confidence interval |
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| Notes [1] - The following analysis populations were predefined: intention to treat (ITT) population (all randomized patients); per protocol (PP) population (patients from the ITT who have the primary outcome measured at 16 weeks and who took at least 80% of all medication doses); and the safety population (all patients who took at least 1 dose of the assigned treatment). |
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Adverse events information
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Timeframe for reporting adverse events |
From 20 september 2017 to 10 March 2021
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Adverse event reporting additional description |
Were reported a total of 238 adverse events (AEs).
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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 |
25.0
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Reporting groups
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Reporting group title |
Placebo
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Reporting group description |
- | ||||||||||||||||||||||||||||||
Reporting group title |
Mirabegron
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Reporting group description |
- | ||||||||||||||||||||||||||||||
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| Frequency threshold for reporting non-serious adverse events: 0% | |||||||||||||||||||||||||||||||
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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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11 Dec 2018 |
The initial version of the SPHERE-HF clinical trial included as exclusion criteria: "Corrected QT interval in ECG >430 ms in men or >450 ms in women", which are the values described of corrected QT interval in the healthy population in some registries (although it is more common to use the values of 450 ms in males and 460 ms in women, as established in clinical practice guidelines [Rautaharju. JACC 2009]).
However, we have found that these criteria exclude a very high percentage of patients with heart failure who could potentially a very high percentage of patients with heart failure who could potentially benefit from this therapy, since it is known that in the presence of heart disease the QT interval is prolonged and also shows greater circadian variation (P.P. Davey, Br Heart J 1994; P Davey, Eur Heart J 2000; Davey PP Clin Sci 2000).
In summary, considering that:
1. Mirabegron does not significantly prolong the QT interval.
2. The SPHERE-HF clinical trial is specifically designed to evaluate the safety of mirabegron treatment in pulmonary hypertension secondary to heart failure, so that you start with the 50 mg dose of mirabegron (dose used for overactive bladder) and an electrocardiogram is mandatory before starting each dose.
3. The current QTc criterion excludes a very high percentage of the target population: patients with heart failure.
We request to modify the exclusion criterion to: "Corrected QT interval on ECG >480 ms", which coincides with the definition of pathological prolongation of the QT interval.
In addition, the same value shall be included in the recommended titration protocol, such that QTc interval >480 ms should be reduced or discontinued, but not titrated upwards.
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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 | |||
