JACC: BASIC TO TRANSLATIONAL SCIENCE VOL. 5, NO. 4, 2020 ª 2020 THE AUTHORS. PUBLISHED BY ELSEVIER ON BEHALF OF THE AMERICAN COLLEGE OF CARDIOLOGY FOUNDATION. THIS IS AN OPEN ACCESS ARTICLE UNDER THE CC BY-NC-ND LICENSE (http://creativecommons.org/licenses/by-nc-nd/4.0/). CLINICAL RESEARCH Design of the b3-Adrenergic Agonist Treatment in Chronic Pulmonary Hypertension Secondary to Heart Failure Trial Ines Garcia-Lunar, MD,a,b,c Isabel Blanco, PHD,d,e Leticia Fernández-Friera, PHD,a,b,f Susanna Prat-Gonzàlez, PHD,g Paloma Jordà, MD,g Javier Sánchez, PHD,a,h Daniel Pereda, PHD,b,g Sandra Pujadas, MD,i Mercedes Rivas, PHD,i Eduard Solé-Gonzalez, MD,j Jorge Vázquez, MD,b,k Zorba Blázquez, MD,l Juan García-Picart, MD,i Pedro Caravaca, MD,l Noemí Escalera, BPT,a,b Pablo Garcia-Pavia, PHD,a,k,m Juan Delgado, PHD,b,l Javier Segovia-Cubero, PHD,b,k Valentín Fuster, PHD,a,n Eulalia Roig, PHD,i Joan Albert Barberá, PHD,d,e Borja Ibanez, PHD,a,b,o Ana García-Álvarez, PHDa,b,g VISUAL ABSTRACT Garcia-Lunar, I. et al. J Am Coll Cardiol Basic Trans Science. 2020;5(4):317–27. HIGHLIGHTS  CpcPH is a relatively common complication of chronic HF, is associated with poor survival, and has no specific pharmacological treatment.  ß3AR stimulation has shown improvement in pulmonary hemodynamics and RV performance in a translational large animal model mimicking this condition.  The SPHERE-HF trial is a Phase II randomized, double-blind clinical trial designed to evaluate the efficacy and safety of mirabegron (oral b3 AR agonist) in patients with CpcPH secondary to HF.  The SPHERE-HF trial will include 80 patients treated with mirabegron or placebo for 16 weeks.  The main outcome is the change in PVR. Secondary outcomes include changes in RV performance, clinical status, NT-proBNP levels, and additional pulmonary hemodynamic parameters. ISSN 2452-302X https://doi.org/10.1016/j.jacbts.2020.01.009 318 Garcia-Lunar et al. JACC: BASIC TO TRANSLATIONAL SCIENCE VOL. 5, NO. 4, 2020 SPHERE-HF Trial Design APRIL 2020:317–27 ABBREVIATIONS SUMMARY AND ACRONYMS b3AR = beta-3 adrenoreceptor Combined pre-and post-capillary hypertension (CpcPH) is a relatively common complication of heart failure CCT = cardiac computed (HF) associated with a poor prognosis. Currently, there is no specific therapy approved for this entity. Recently, tomography treatment with beta-3 adrenergic receptor (b3AR) agonists was able to improve pulmonary hemodynamics and cGMP = cyclic guanosine right ventricular (RV) performance in a translational, large animal model of chronic PH. The authors present the monophosphate design of a phase II randomized clinical trial that tests the benefits of mirabegron (a clinically available b3AR CMR = cardiac magnetic agonist) in patients with CpcPH due to HF. The effect of b3AR treatment will be evaluated on pulmonary resonance hemodynamics, as well as clinical, biochemical, and advanced cardiac imaging parameters. (Beta3 Agonist CpcPH = combined pre- and Treatment in Chronic Pulmonary Hypertension Secondary to Heart Failure [SPHERE-HF]; NCT02775539) post-capillary pulmonary hypertension (J Am Coll Cardiol Basic Trans Science 2020;5:317–27) © 2020 The Authors. Published by Elsevier on behalf ECG = electrocardiography of the American College of Cardiology Foundation. This is an open access article under the CC BY-NC-ND HF = heart failure license (http://creativecommons.org/licenses/by-nc-nd/4.0/). IpcPH = isolated post-capillary P pulmonary hypertension ITT = intention to treat ulmonary hypertension (PH) is a com- with specific pulmonary vasodilators [i.e., prosta- LHD = left heart disease mon complication of heart failure noids (10) and endothelin receptor blockers (11,12)] in LV = left ventricular (HF) (1,2) that results in more severe cohorts with HF or PH secondary to HF have not LVEF = left ventricular symptoms, worse exercise tolerance, and shown positive results, primarily because of ejection fraction increased risk of death (3–5). Initially, this concomitant systemic hypotension and hepatic NT-proBNP = N-terminal isolated post-capillary PH (IpcPH) is purely toxicity. Although preliminary data from small single- prohormone of brain passive but has the potential to progress to center studies (13,14) that tested phosphodiesterase natriuretic peptide combined pre- and post-capillary PH type 5 inhibitors in PH secondary to HF were prom- NYHA = New York Heart (CpcPH), a progressive disease characterized ising, more recent evidence (15–17) strongly discour- Association by significant vasoconstriction and vascular ages their use in this setting. In addition, neutral PAP = pulmonary artery pressure remodeling with a worse prognosis than findings have been reported for cyclic guanosine IpcPH (6,7). Although IpcPH can be treated monophosphate (cGMP) stimulation in PH secondary PH = pulmonary hypertension by focusing only on the underlying condition to HF, either with preserved or reduced left ventric- PP = Per protocol (8), CpcPH requires treatment of both pulmo- ular ejection fraction (LVEF) (18,19). Therefore, new PVR = pulmonary vascular resistance nary vascular remodeling and the primary treatments are needed for CpcPH. heart disease. The sympathetic nervous system is central to the RV = right ventricle Currently, there are no specific pharma- neurohumoral regulation of cardiovascular function cological therapies approved for patients and is implicated in many cardiopulmonary diseases. with CpcPH (8,9). Clinical studies performed Beta-3 adrenoreceptor (b3AR) expression has been From the aCentro Nacional de Investigaciones Cardiovasculares (CNIC), Madrid, Spain; bCentro de Investigación Biomédica en Red de Enfermedades Cardiovasculares (CIBERCV), Madrid, Spain; cHospital Universitario Quirónsalud Madrid, UEM, Madrid, Spain; d Department of Pulmonary Medicine, Hospital Clínic-IDIBAPS, Barcelona, Spain; eCentro de Investigación Biomédica en Red de Enfermedades Respiratorias (CIBERES), Madrid, Spain; fHM Hospitales-Centro Integral de Enfermedades Cardiovasculares HM- CIEC, Madrid, Spain; gInstitut Clinic Cardiovascular, IDIBAPS, Hospital Clínic, University of Barcelona, Barcelona, Spain; hPhilips Healthcare Iberia, Madrid, Spain; iCardiology Department, Hospital Santa Creu i Sant Pau, IIb-Sant Pau, Universitat Autonoma de Barcelona, Barcelona, Spain; jCardiology Department, Hospital del Mar, Barcelona, Spain; kCardiology Department, University Hospital Puerta de Hierro, University Autonoma de Madrid, Madrid, Spain; lCardiology Department, University Hospital 12 de Octubre, Universidad Complutense, Madrid, Spain; mUniversity Francisco de Vitoria (UFV), Pozuelo de Alarcon, Spain; nZena and Michael A. Wiener Cardiovascular Institute, Icahn School of Medicine at Mount Sinai, New York, New York; and oIIS-Fundación Jiménez Díaz University Hospital, Madrid, Spain. The SPHERE-HF trial is an investigator-initiated noncommercial trial inde- pendent of the pharmaceutical industry. This work was funded by a grant from Fundació La Marató de TV3 (20151730-31-32). The CNIC is supported by the Ministerio de Ciencia, Innovacion y Universidades and the Pro CNIC Foundation and is a Severo Ochoa Center of Excellence (SEV-2015-0505). IDIBAPS belongs to the CERCA Programme and receives partial funding from the Gen- eralitat de Catalunya. Drs. Ibanez, García-Álvarez, and Fuster are co-inventors of a patent for the use of beta-3 agonists for the treatment of pulmonary hypertension. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose. The authors attest they are in compliance with human studies committees and animal welfare regulations of the authors’ institutions and Food and Drug Administration guidelines, including patient consent where appropriate. For more information, visit the JACC: Basic to Translational Science author instructions page. Manuscript received September 27, 2019; revised manuscript received January 2, 2020, accepted January 2, 2020. JACC: BASIC TO TRANSLATIONAL SCIENCE VOL. 5, NO. 4, 2020 Garcia-Lunar et al. 319 APRIL 2020:317–27 SPHERE-HF Trial Design demonstrated in the human myocardium and ves- in RV performance; 3) improvement in clinical status; sels, and it has been described to be upregulated in and 4) no increase in adverse events. left heart disease (LHD) (20,21). Like other adrenor- STUDY ENDPOINTS. E f fi c a c y m e a s u r e s . The pri- eceptors, b 3ARs are coupled to G proteins, and the mary outcome is the change in PVR on right heart downstream activated pathway includes nitric oxide catheterization, calculated in Wood units as: (mean synthase, nitric oxide-activated guanylyl cyclase, pulmonary artery pressure (PAP) [mm Hg]  pulmo- and cGMP synthesis, as well as increased cyclic nary capillary wedge pressure [mm Hg])/cardiac adenosine monophosphate synthesis (22). Loss of output [l/min]) from baseline to week 16. Secondary cGMP and cyclic adenosine monophosphate outcomes are change from baseline to week 16 in signaling represents a hallmark in PH. It is known clinical status (measured by 6-min walk distance, that within the pulmonary circulation, cyclic nucle- New York Heart Association [NYHA] functional class, otides exert several favorable effects, including quality of life evaluated with the Spanish version of vasodilatation, inhibition of smooth muscle cell the Kansas City Cardiomyopathy Questionnaire, and proliferation, and prevention of platelet aggregation the dyspnea Borg scale score), other hemodynamic (23). variables assessed by right heart catheterization In recent years, several publications have demon- (mean PAP, transpulmonary gradient, diastolic pres- strated the cardioprotective effect of b3AR stimula- sure gradient, and cardiac output), RV performance tion in different experimental models of (RV ejection fraction and cardiac output by cardiac ischemia-reperfusion injury (24–26) and HF (27–29). magnetic resonance [CMR] or cardiac computed to- Therefore, b3ARs have emerged as a potential thera- mography [CCT]), as well as plasmatic levels of N- peutic target in cardiovascular diseases. Recent terminal pro-hormone of brain natriuretic peptide experimental research has demonstrated that treat- (NT-proBNP). ment with b3AR agonists produces a beneficial effect Safety measures include hospital admissions for on hemodynamics, right ventricular (RV) remodeling, HF or respiratory failure, death, urgent heart trans- and pulmonary vascular proliferation in a trans- plantation, initiation of intravenous therapy due to lational porcine model of post-capillary chronic PH worsening HF (diuretics or inotropic drugs), adverse (30). In addition, several Phase II and III randomized events, and adverse drug reactions, as well as mon- clinical trials (31–37) have already confirmed the good itorization of heart rate and the QTc interval on safety profile of the oral b 3AR agonist mirabegron in electrocardiography (ECG) (by Framingham method). healthy subjects and in patients with overactive External monitoring of all clinical events and ECG bladder syndrome. Mirabegron, the selective oral acquisitions will be performed. b3AR agonist tested in the present trial, is currently STUDY POPULATION AND INCLUSION/EXCLUSION approved for the treatment of overactive bladder CRITERIA. Patients have been identified and syndrome in Europe, Japan, and America. A recent recruited from 4 different tertiary hospitals across study has also demonstrated a good safety profile of Spain, all of which have a reference HF Unit. Inclu- mirabegron in patients with HF and reduced LVEF sion and exclusion criteria are presented on Table 1. (38). At the first protocol, an exclusion criterium of QTc Based on the previously described concepts and interval on ECG >430 ms in men and >450 in women evidence and the positive results of pre-clinical was included as a general safety standard. This cri- research, we designed a multicenter placebo- terion was later modified by an amendment to QTc controlled Phase II randomized clinical trial to eval- >480 ms, based on the high percentage of patients uate the efficacy and safety of mirabegron in patients with CpcPH who were excluded at baseline and the with chronic CpcPH secondary to HF. absence of data that suggested that mirabegron METHODS significantly increased QTc. STUDY DESIGN. This trial is a Phase II double-blind STUDY HYPOTHESIS. The main hypothesis of the multicenter, placebo-controlled randomized controlled SPHERE-HF ( b3 Adrenergic Agonist Treatment in trial. It consists of a screening phase and the ran- Chronic Pulmonary Hypertension Secondary to domized double-blind 16-week period (main Heart Failure) trial is that maintenance treatment study), which includes a dose titration phase and a with a selective b 3AR agonist (mirabegron) in patients maintenance phase (Figure 1). with PH secondary to HF compared with placebo will During the screening phase, eligible patients, usu- result in a beneficial effect due to: 1) a reduction in ally identified after a right heart catheterization, are pulmonary vascular resistance (PVR); 2) an increase invited to participate in the study. After providing 320 Garcia-Lunar et al. JACC: BASIC TO TRANSLATIONAL SCIENCE VOL. 5, NO. 4, 2020 SPHERE-HF Trial Design APRIL 2020:317–27 T A B L E 1 Inclusion and Exclusion Criteria Inclusion Criteria Exclusion Criteria Written informed consent Noncoronary cardiac surgery (e.g., valvular surgery) or noncoronary structural percutaneous procedure (e.g., Mitraclip) within the 12 months preceding recruitment or scheduled. Age $18 years of age Myocardial infarction or coronary revascularization within the 3 months preceding recruitment. HF with reduced, intermediate or preserved LVEF, according to the CRT implantation within the 6 months preceding recruitment definition of the European Society of Cardiology guidelines. Combined pre- and post-capillary PH determined by RHC showing the following: PCWP or LVEDP $15 mm Hg. Mean PAP $25 mm Hg; and: Sinus tachycardia or uncontrolled atrial fibrillation (HR >100 beats/min). PVR $3 WU and/or diastolic gradient $7 mm Hg, or transpulmonary gradient $12 mm Hg NYHA functional class IIIV Uncontrolled systemic hypertension (systolic BP >180 mm Hg or diastolic BP >110 mm Hg) or symptomatic hypotension (systolic BP <90 mm Hg). On optimized evidence-based pharmacological treatment Diagnosis of infiltrative cardiomyopathy. Stable clinical condition defined as no changes in therapeutic regimen Pre-menopausal women who have not undergone total hysterectomy for HF or hospitalization in the 30 days preceding recruitment and no current plan for changing therapy.* Expected survival <1 yr due to a disease other than HF. Severe renal failure (GFR <30 ml/min/1.73 m2). Severe hepatic impairment (transaminase elevation>3 times ULN). Prolonged QTc interval on the ECG (>430 ms in men or >450 ms in women)† Concomitant use with specific pulmonary vasodilators (sildenafil, bosentan, macicentan, riociguat, or other endothelin receptor blockers, phosphodiesterase 5 inhibitors or guanylate cyclase stimulators). Treatment with digoxin, flecainide, propafenone, dabigatran, tricyclic antidepressants or other CYP2D6 inhibitors (other than b-blockers). Severe COPD (FEV1/FVC ratio <0.7 together with FEV1 <50% predicted value). Severe restrictive lung disease (TLC <50%) Participation in another clinical trial Known allergy to mirabegron or any of the excipients *In the case of heart failure (HF) with preserved left ventricular ejection fraction (LVEF) it refers to an adequate control of comorbidity and optimized fluid status. †This criterion was changed by an amendment to QTc >480 ms. BP ¼ blood pressure; COPD ¼ chronic obstructive pulmonary disease; CRT ¼ cardiac resynchronization therapy; FEV1 ¼ forced expiratory volume in the first second; FVC ¼ forced vital capacity; GFR ¼ glomerular filtration rate; HR ¼ heart rate; LVEDP ¼ left ventricular end-diastolic pressure; NYHA ¼ New York Heart Association; PAP ¼ pulmonary artery pressure; PCWP ¼ pulmonary capillary wedge pressure; PVR ¼ pulmonary vascular resistance; RHC ¼ right heart catheterization; TLC ¼ total lung capacity; ULN ¼ upper limit of normal; WU ¼ Wood units. written informed consent, patients undergo the once-daily dosing with mirabegron. Thereafter, following baseline procedures and assessments (all medication dose is titrated every 2 weeks for 8 weeks must be completed within 4 weeks before random (visits 3, 4, and 5) based on patients’ monitoring of allocation): demographic and medical history data blood pressure, heart rate, QTc interval, blood anal- collection; physical examination (including blood ysis, and clinical status assessed at that visit (Table 3 pressure, heart rate, and pulse oximetry); NYHA shows the recommended titration algorithm). At the functional class; blood sample analysis including end of the dose titration phase (visit 6), all NT-proBNP; ECG; echocardiography; right heart patients are expected to have reached their optimal catheterization; 6-min walking test, and CMR. Those dose. To assure blinding of the treatment arms, pa- patients with formal contraindications for CMR can tients allocated to the placebo group undergo titra- undergo a dedicated CCT examination to measure RV tion from visit 3 onwards, following the same volumes and function (Table 2, Figure 2). algorithm. Patients who fulfill all inclusion criteria and none During the maintenance phase (8 weeks), patients of the exclusion criteria are randomized to receive continue receiving the same dose assigned at visit 6, either mirabegron (50 mg) or placebo once daily in a unless a decrease in dose is required for safety pur- blinded fashion (visit 0). Visit 1 represents the day of poses. An intermediate clinical visit is performed the first study medication dose and must take place halfway through the maintenance phase (visit 7). At in the 5 days after visit 0. A safety visit is performed visit 8 (end of the study), patients undergo all study 1 week after initiation of therapy (visit 2) because, examinations performed at baseline and stop the according to the medication technical sheet, steady- study medication. The last visit (visit 9) takes place state concentrations are achieved at 7 days of 30 days after the last study medication dose for JACC: BASIC TO TRANSLATIONAL SCIENCE VOL. 5, NO. 4, 2020 Garcia-Lunar et al. 321 APRIL 2020:317–27 SPHERE-HF Trial Design F I G U R E 1 Summary of the Study Conduct security monitoring, according to clinical trials and expiration. The bottles are kept in the clinical regulation. trials area in conservation conditions (atmosphere Table 2 shows a detailed calendar of the procedures temperature <25 o C). that are performed at each study visit. Polyethylene bottles containing 30 capsules of SAMPLE SIZE. A sample size sample size of 31 sub- mirabegron or placebo are labeled in a blinded jects per group achieves 80% power to reject the null manner, so both the physicians and patients are hypothesis of zero treatment difference when the blinded to the study medication. Thereby, titration is 2-sided significance level (alpha) is 0.05 and 2.1 Wood performed in the same way for both active drug and units, which are the minimal clinically important placebo by increasing the number of capsules a day, difference between groups. We assumed a SD of 3.2 and there is no option that unblinding is lost in the up Wood units in PVR (39) and a correlation between titration phase. baseline and 16 weeks of 0.6. Assuming a 20% STATISTICAL METHODS. Randomization procedure. dropout rate, the estimated number of patients Participants will be assigned, on an individual basis, needed is 40 per group (80 total). Calculations were to mirabegron or placebo using randomly selected made using the power.t.test function available in R block sizes stratified by center using the Blockrand software (R Foundation, Vienna, Austria). package (R Foundation). The randomization list will Manufacturing of study medication. Manufacturing of be provided exclusively to the pharmacy department mirabegron and placebo is carried out in the phar- responsible for the medication preparation, which maceutical area of the Hospital Clínic Pharmacy department. The excipient for placebo capsules T A B L E 2 Overview of Study Visits and Examinations (mixture of microcrystalline cellulose and colloidal V0V1 V2 V3 V4 V5 V6 V7 V8 V9 silica) is received with the corresponding certificate Informed consent X of analysis from the manufacturer (Fagron Iberica Inclusion/exclusion criteria X S.A.U, Tarrasa, Spain). The material the lot number Demographic variables, prior medical X and expiration date are verified for each entry, and history and medication the corresponding certificate of analysis is archived. Anamnesis X X X X X X X X X Similarly, at the reception of mirabegron (Betmiga; Physical examination X X X X X X X X X bought from Astelas Pharma [Chuo, Tokyo, Japan] Laboratory X X X X X X ECG X X X X X X X X X for 28.9V/box containing 30 pills of 50 mg of Bet- Kansas City Cardiomyopathy Questionnaire X X miga), the batch and expiration date are checked Echocardiogram X X and recorded. Betmiga pills are taken out of the Right heart catheterization X X blisters and automatically encapsulated (a single pill NT-proBNP X X into a capsule). Similarly, the excipient is included 6-min walking test X X in the capsules. Immediately, capsules including CMR X X mirabegron or excipient are introduced in poly- CMR ¼ cardiac magnetic resonance; ECG ¼ electrocardiogram; NT-proBNP ¼ N-terminal pro-hormone of brain ethylene bottles (30 capsules each) that are labeled natriuretic peptide; V ¼ visit. as study medication, including the batch number 322 Garcia-Lunar et al. JACC: BASIC TO TRANSLATIONAL SCIENCE VOL. 5, NO. 4, 2020 SPHERE-HF Trial Design APRIL 2020:317–27 F I G U R E 2 Multimodality Imaging Evaluation of RV Performance in SPHERE-HF Trial (A) Right ventricular (RV) speckle trackingderived strain from an apical 4-chamber view on echocardiography. (B and C) End-diastolic and end-systolic frames from the cine sequence at the mid-ventricular level to calculate biventricular volumes and ejection fraction with cardiac magnetic resonance (CMR). (D and E) T1 maps before (D) and 15 min after contrast administration (E) for estimation of extracellular volume using CMR. (F and G) Cardiac computed tomographic images from end- diastolic and end-systolic frames to calculate biventricular volumes and ejection fraction in a patient who could not undergo CMR due to an implantable cardiac resynchronization therapy device. SPHERE-HF ¼ b3 Adrenergic Agonist Treatment in Chronic Pulmonary Hypertension Secondary to Heart Failure. will prepare the medication kits by identifying them group who have the final (16-week) measurement of with a unique sequential number for the entire study the primary outcome and who have taken at least and will provide the kits to the centers. Researchers 80% of all the medication doses; and safety pop- will assign received medication kits in a sequential ulationdall patients who have taken $1 doses of the order and record the kit number provided to each assigned treatment. patient in the data collection system. Baseline descriptive statistics will be calculated S t a t i s t i c a l a n a l y s i s . The following analysis pop- according to standard methods on the ITT and PP ulations are pre-defined for this study: intention to populations. Qualitative variables will be described as treat (ITT) populationdall randomized patients; per absolute number (n) and frequency (%), whereas protocol (PP) populationdpatients from the ITT quantitative variables will be described by mean  SD T A B L E 3 Recommended Medication Dose Titration Algorithm Clinical Assessment Recommended Action Normal BP (systolic BP $95 and #135 mm Hg) AND HR #90 beats/min AND QTc interval* <430 ms in men Up titrate study medication in 50 mg/day or <450 ms in women AND blood analysis within normality AND patient asymptomatic If the patient develops any of the following: significant hypotension (systolic BP <80 mm Hg) or hypertension Reduce or stop study medication dose (systolic BP >145 mm Hg) OR tachycardia (HR >100 beat/min) OR prolonged QTc interval* (>430 ms in men or >450 ms in women) OR worsening of renal function/transaminase elevation on blood analysis OR symptoms associated with medication If the patient presents with mild hypotension (systolic BP $80 and <90 mm Hg) OR mild hypertension Maintain study medication dose (systolic BP >135 and #145 mm Hg) AND/OR HR 90100 beats/min (with a QTc interval* <430 ms in men and <450 ms in women) AND blood analysis is within normality *This criterion was changed by an amendment to QTc >480 ms for both sexes. Abbreviations as in Tables 1 and 2. JACC: BASIC TO TRANSLATIONAL SCIENCE VOL. 5, NO. 4, 2020 Garcia-Lunar et al. 323 APRIL 2020:317–27 SPHERE-HF Trial Design or median (interquartile range), depending on Q u a l i t y o f l i f e q u e s t i o n n a i r e . The Kansas City normality (assessed using the Shapiro-Wilk test). Ef- Cardiomyopathy Questionnaire, which has been ficacy measures will be calculated on the ITT and PP validated in the Spanish population, will be used to analyses. The treatment effect on the primary assess quality of life. outcome measure will be analyzed using a linear Physical e x a m i n a t i o n . Blood pressure will be regression model that includes the baseline value, measured at every visit using an automated sphyg- treatment, baseline  treatment interaction, center, momanometer in a quiet room. Three measurements and center  treatment interaction. Interaction terms will be performed over a 10-min period, and the will be removed if the Wald test is not statistically average between the second and third measurement significant (p > 0.10). The efficacy analyses done on will be registered. Heart rate and oxygen saturation the PP set will be considered confirmatory (main (using a pulse oxymeter) will be also entered into the analyses). For the ITT population, in those cases with electronic case report form. Patients will be weighed missing final values of the primary outcome measure, on every study visit, and functional class (following these values will be replaced by the baseline data (last the NYHA classification), as well as HF signs and observation carried forward). symptoms will be recorded. The following exploratory analyses of the primary B l o o d s a m p l e s . A venous sample will be obtained at outcome measure will be contemplated: LVEF visits 0, 3, 4, 5, 6, and 8 and tested for complete blood (LVEF <40% vs. $40%); and the maximum tolerated count, serum glucose, as well as renal and liver dose (mg/d) subgroups and their interaction with function. NT-proBNP measurement will also be per- treatment. Secondary outcome measures will be formed at visits 0 and 8. analyzed similarly using linear models for quantita- E C G . Heart rhythm, heart rate, QT, and QTc interval tive normal variables or generalized models for will be measured. quantitative non-normal variables and logistic E c h o c a r d i o g r a p h y . Studies will be performed ac- regression for dichotomous values. The analysis of cording to standard American Society of Echocardi- the secondary variables will be carried out using the ography and European Association of Cardiovascular available information, without missing imputation Imaging guidelines, with special dedication to the techniques. evaluation of RV performance (41,42). The acquisition A descriptive analysis will be performed to eval- protocol is standardized across all centers, and uate safety of the treatment using the safety popu- studies are digitally stored for dedicated offline lation. No interim analyses are planned. A 2-tailed analysis at the Imaging Core Laboratory located at p value < 0.05 will be considered statistically signif- Centro Nacional de Investigaciones Cardiovasculares. icant, unless otherwise specified. Left ventricular (LV) volumes and ejection fractions will be measured using the modified Simpson rule DESCRIPTION OF THE STUDY PROCEDURES AND (biplane method). Left and right atrial areas will be EXAMINATIONS. R i g h t h e a r t c a t h e t e r i z a t i o n . The obtained at ventricular end-systole, excluding the procedure will be performed using a Swan-Ganz pulmonary vein confluence and the left atrial catheter introduced via the internal jugular vein us- appendage. RV dimensions, end-systolic and end- ing a standard methodology. Hemodynamic mea- diastolic RV areas, and the tricuspid annular plane surements will include right atrial pressure, systolic, systolic excursion will be measured from a RV- diastolic, and mean PAP, as well as pulmonary capil- focused apical 4-chamber view. Fractional area lary wedge pressure at end-expiration. Zero level will change will be calculated as the difference in RV end- be set at the level of the anterior axillar line while diastolic area and RV end-systolic area divided by the lying flat; 2 different mean PAP values will be regis- RV end-systolic area. RV index of myocardial perfor- tered over a 5- to 10-min period, and the average mance (Tei index) and the tricuspid lateral annular calculated. Cardiac output will be quantified by the systolic velocity wave (S’) will be measured using thermodilution method (5 measurements, average of Doppler tissue imaging velocity of the lateral 3, excluding the highest and lowest values). tricuspid annulus. Valvular disease and diastolic 6 - m i n w a l k i n g t e s t . Tests will be carried out function will be graded according to the American following the recommendations of the American and Society of Echocardiography and European Associa- European Respiratory Societies (40). Patients will be tion of Cardiovascular Imaging standards (43–45). A instructed to walk along a 30-m long corridor and to 3-beat 2-dimensional digital clip of a RV-focused, walk as far as possible for 6 min. Tests will be su- 4-chamber view will be acquired for quantification pervised by a nurse, and heart rate and oxygen of RV strain by speckle tracking echocardiography saturation will be recorded. (Figure 2A). All analyses will be performed using the 324 Garcia-Lunar et al. JACC: BASIC TO TRANSLATIONAL SCIENCE VOL. 5, NO. 4, 2020 SPHERE-HF Trial Design APRIL 2020:317–27 EchoPAC v112 (GE Healthcare, Chicago, Illinois) or by blinded investigators in the Imaging Core Labora- Xcelera R4.1 and QLAB 10.2 (Philips, Amsterdam, the tory at CNIC. On cine images, end-diastolic and end- Netherlands) software. systolic frames will be selected based on visual C M R . CMR studies will be performed with either 1.5- assessment of largest and smallest LV volumes, or 3.0-T magnets, using dedicated surface coils for respectively, and on the opening or closing of atrio- cardiac studies and retrospective electrocardio- ventricular and semilunar valves. Biventricular graphic gating. The acquisition protocol is standard- endocardial contours will be manually traced in end- ized across all centers, and all studies are digitally diastole and end-systole, and Simpson’s method will stored for dedicated offline analysis at the Imaging be used to automatically calculate end-diastolic vol- Core Laboratory located at Centro Nacional de umes, end-systolic volumes, and ejection fractions. Investigaciones Cardiovasculares (CNIC) (Madrid, RV trabeculations will be adjudicated to the blood Spain). pool (Figures 2B and 2C). Similarly, the inner contours The CMR examination includes the following se- of the main pulmonary artery cross section will be quences. A steady-state free precession cine sequence outlined in each cardiac phase. Through integration is used to acquire 15 contiguous short-axis slices of pulmonary artery areas and flow, the following covering both ventricles from base to apex and parameters will be quantified: peak velocity; average reconstructed into 25 cardiac phases each for the velocity during the complete cardiac cycle; minimum evaluation of biventricular volumes and function. and maximum areas; and pulmonary artery net Two-dimensional flow imaging (phase contrast) is forward volume. RV-arterial coupling (the ratio of performed perpendicular to the main pulmonary ar- pulmonary artery effective elastance to RV maximal tery with a velocity-encoded gradient echo sequence end-systolic elastance) will be estimated as (end- and an upper velocity limit of 100 cm/s (with further systolic volume/stroke volume) (47). Regions of in- increases for any signal aliasing). For this purpose, 2 terest will be drawn on T1 maps in the myocardial double-oblique orthogonal views oriented along the anterior and inferior RV insertion points, interven- main axis of the pulmonary artery trunk are acquired tricular septum, LV lateral wall and LV cavity blood with a standard steady-state free precession cine pool before and after contrast administration for sequence and used as the reference to prescribe a estimation of the extracellular volume, as previously plane truly perpendicular to the main pulmonary ar- described (Figures 2D and 2E) (48). tery for the acquisition of phase contrast images. Care C C T . CCT studies are performed using at least a 64- is taken to ensure that the imaging plane remains slice scanner with retrospective electrocardiographic between the pulmonary valve and pulmonary artery gating mode acquisition (ideally with modulation bifurcation throughout the cardiac cycle. In addition, dose). CCT images are acquired from the level of the aortic velocity and LV cardiac output are systemati- aortic arch to the dome of the diaphragm in a breath- cally measured (46). For delayed gadolinium hold mode. Nonionic iodinated contrast agent enhancement imaging, patients receive an intrave- (approximately 80 ml) is injected at a rate of 5 ml/s nous bolus of 0.125 mmol/kg of gadolinium followed with a power injector, followed by a saline 40 ml by 20 ml of saline. After 5 to 10 min, contiguous short- flush. A bolus tracking technique is used to trigger axis views matching the cine images are acquired image acquisition once attenuation in a region of in- using a phase-sensitive inversionrecovery fast terest placed in the descending aorta has reached a gradient echo sequence for the evaluation of delayed pre-set threshold of 100 HU. gadolinium enhancement. Typical breath-hold times Axial images are reconstructed with an image ma- range from 8 to 14 s. In patients with an inability to trix of 512  512 pixels and a slice thickness of 1.25 mm perform such breath-holds, delayed gadolinium from 0% to 90% of the cardiac cycle to calculate RV enhancement images are repeated with a single-shot function. Post-processing of CCT images will be per- inversionrecovery steady-state free precession formed on a dedicated workstation with specific RV sequence during free breathing. T1 mapping se- function quantification package (IntelliSpacePortal quences will be acquired just before contrast admin- v9.0, Philips) (Figures 2F and 2G). istration and 15 min after contrast administration in a short-axis view at the level of the papillary muscles DURATION OF THE STUDY. The SPHERE-HF clinical for estimation of the extracellular volume fraction. trial started recruitment in June 2017, and it is ex- C M R a n a l y s i s . Cine, 2-dimensional flow imaging and pected that the inclusion phase will end by June delayed enhancement will be analyzed using 2020. As of December 18, 2019, a total of 61 patients specialized software (IntelliSpacePortal v9.0, Philips) have been included in the study. JACC: BASIC TO TRANSLATIONAL SCIENCE VOL. 5, NO. 4, 2020 Garcia-Lunar et al. 325 APRIL 2020:317–27 SPHERE-HF Trial Design DISCUSSION required optimization of HF therapy before initi- ating the study medication; and 4) most lacked a PH associated with HF has repeatedly been shown to comprehensive evaluation of hemodynamics, exer- decrease survival, particularly in patients with CpcPH cise capacity, and imaging of the RV. Based on this (6,39). Although IpcPH is entirely reversible when evidence, targeted treatment using pulmonary pulmonary arterial wedge pressure is normalized by arterial hypertension-approved therapies on PH medical or surgical interventions, this is not the case secondary to LHD is discouraged by the current PH for CpcPH, due to associated pulmonary arterial guidelines (8). remodeling. The latter correlates with pulmonary The SPHERE-HF trial addresses a new approach vascular gradients and increased PVR (49). Approxi- to treat PH secondary to HF and overcomes most of mately 12% to 14% of patients with PH and HF present the previously mentioned limitations. SPHERE-HF is with CpcPH, a prevalence similarly distributed in based on solid large animal experimentation data reduced or preserved HF (6). As underlined by Van- (30). SPHERE-HF is a multicenter randomized derpool and Naeije (50), knowledge of the specific controlled trial that targets patients with LHD and phenotype of CpcPH is of great importance to the confirmed PH with an established pre-capillary design of future trials of targeted therapies for PH and component (PVR >3 Wood units and/or diastolic HF. gradient $7 mm Hg or transpulmonary Several randomized controlled trials tested the gradient $12 mmHg, criteria based on PH guidelines effect of pulmonary vasodilators in HF but few of valid at the time of the trial design). In this way, them focused in patients with confirmed PH and SPHERE-HF targets those patients who are most only a minority of studies focused on CpcPH. likely to develop pulmonary vascular remodeling Studies that evaluated the effect of prostanoids and impaired RV function, and therefore, may (epoprostenol) (10) and endothelin-1 receptor an- potentially benefit most from b 3AR stimulation. As tagonists (bosentan) (11,51) in patients with opposed to other trials, the primary outcome mea- advanced HF and severe LV systolic dysfunction sure in SPHERE-HF is the change in PVR rather than were terminated early due to an increased rate of mean PAP. We consider PVR a more robust adverse events in the investigational drug group endpoint because it recapitulates pulmonary pres- compared with the control group. In the recent sures and the degree of RV dysfunction and has MELODY (Macitentan in Pulmonary Hypertension demonstrated prognostic relevance in PH (52), and due to Left Ventricular Dysfunction) trial (12), particularly in PH secondary to LHD (3,8,9,53–55). In which randomized 63 patients with CpcPH to addition, cardiac imaging is a critical part of the macitentan or placebo, there were no differences in SPHERE-HF clinical trial. The effect of mirabegron the main endpoint (composite of fluid retention or on RV performance will be evaluated using state-of- worsening in NYHA functional class) between the art imaging techniques (CMR, CCT, and echo- groups. Phosphodiesterase-type 5 inhibitors also cardiography) and several markers of subclinical failed to show a consistent effect in PH secondary myocardial disease (e.g., speckle trackingderived to HF (13–17). Moreover, in the recent Spanish strain and extracellular volume quantified by T1- multicenter SIOVAC (Sildenafil for Improving Out- mapping CMR) will be assessed to quantify subtle comes After Valvular Correction) trial that included changes in RV function under treatment. Finally, 200 patients with residual PH after surgically despite the limitations derived from the sample treated valvular heart disease, sildenafil was asso- size, important patient-centric outcomes (e.g., ciated with worse outcomes than placebo (17). functional class or quality of life) have been pre- Regarding soluble guanylate cyclase stimulators specified as secondary outcomes of the current (riociguat), neutral findings were reported in PH SPHERE-HF. secondary to HF with preserved and reduced LVEFs (18,19). Several limitations of the previous trials STUDY LIMITATIONS. First, the trial focuses in pa- should be noted: 1) in most of them, the target tients with CpcPH by including patients with population was not selected based on the pulmo- reduced or preserved LVEF based on a common he- nary hemodynamic status (confirmed diagnosis of modynamic and biological phenotype (56). Because PH) but included the full spectrum of patients with we recognize that it may include some heterogene- LHD, and only a minority were targeted at patients ity, a pre-specified subanalysis regarding LVEF with CpcPH; 2) most studies were single center, (<40% vs. $40%) will be considered. Second, this is which limited the extrapolation of results; 3) few a proof-of-concept trial with a hemodynamic 326 Garcia-Lunar et al. JACC: BASIC TO TRANSLATIONAL SCIENCE VOL. 5, NO. 4, 2020 SPHERE-HF Trial Design APRIL 2020:317–27 endpoint; if positive, a Phase III trial with clinical PERSPECTIVES patient-center endpoints will be performed. The dose selection for this study was based on COMPETENCY IN MEDICAL KNOWLEDGE: previously reported safety data, and particularly, CpcPH is a relatively common complication of chronic cardiovascular safety for mirabegron up to 200 mg/ HF that is associated with poor survival and no specific day has been established (31–33,38). pharmacological treatment. Recently, it was shown CONCLUSIONS that b3AR stimulation improves pulmonary hemody- namics and RV performance in a translational large SPHERE-HF will test the hypothesis that in patients animal model mimicking this condition. The SPHERE- with CpcPH secondary to HF, therapy with a b3AR HF trial is a phase-2 randomized clinical trial designed agonist improves pulmonary hemodynamics, RV to evaluate the efficacy and security of mirabegron performance, and functional status with a good safety (oral b3AR agonist) in patients with CpcPH secondary profile. to HF. TRANSLATIONAL OUTLOOK: SPHERE-HF is a ADDRESS FOR CORRESPONDENCE: Dr. Ana García- pilot clinical trial that has been developed after Álvarez, Cardiology Department. Clinic Cardiovascu- experimental evidence of the beneficial effect of lar Institute, Hospital Clínic, Villarroel 170, 08027 beta3AR agonist treatment in chronic PH, following Barcelona, Spain. E-mail: agarciaa@cnic.es OR our translational program at CNIC. 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A proof-of-concept study: tricular diastolic function by echocardiography: an mirabegron, a new therapy for overactive bladder. update from the American Society of Echocardi- KEY WORDS adrenoreceptors, imaging, Neurourol Urodyn 2013;32:1116–22. ography and the European Association of pulmonary hypertension, treatment