HYPERION: Study of Sotatercept in Newly Diagnosed Intermediate- and High-risk PAH Patients

Sponsor

Acceleron Pharma Inc. (a wholly owned subsidiary of Merck Sharp and Dohme, a subsidiary of Merck & Co., Inc.) (Industry)

Overall Status

Recruiting

CT.gov ID

NCT04811092

Collaborator

(none)

662

Enrollment

100

Locations

Arms

77.5

Anticipated Duration (Months)

6.6

Patients Per Site

0.1

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

The objective of this study is to evaluate the effects of sotatercept treatment (plus background PAH therapy) versus placebo (plus background PAH therapy) on time to clinical worsening (TTCW) in participants who are newly diagnosed with PAH and are at intermediate or high risk of disease progression.

Condition or Disease	Intervention/Treatment	Phase
Pulmonary Arterial Hypertension	Drug: Sotatercept Other: Placebo	Phase 3

Detailed Description

Study A011-13 is Phase 3, randomized, double-blind, placebo-controlled study to evaluate sotatercept when added to background PAH therapy in newly diagnosed intermediate- or high risk PAH patients.

Participants enrolled in the study will have a diagnosis within 6 months of study screening of symptomatic PAH (WHO Group 1, classified as FC II or III) and presentation of idiopathic or heritable PAH, PAH associated with connective tissue diseases (CTD), drug- or toxin- induced PAH, post shunt correction PAH, or PAH presenting at least 1 year following the correction of congenital heart defects.

Study Design

Study Type:

Interventional

Anticipated Enrollment :

662 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

Double (Participant, Investigator)

Masking Description:

Double-blind

Primary Purpose:

Treatment

Official Title:

A Phase 3, Randomized, Double-blind, Placebo-controlled Study to Evaluate Sotatercept When Added to Background Pulmonary Arterial Hypertension (PAH) Therapy in Newly Diagnosed Intermediate- and High-risk PAH Patients

Actual Study Start Date :

Mar 18, 2022

Anticipated Primary Completion Date :

Jun 30, 2028

Anticipated Study Completion Date :

Aug 31, 2028

Arms and Interventions

Arm	Intervention/Treatment
Placebo Comparator: Placebo plus background PAH therapy Administered subcutaneously (SC) every 21 days plus background PAH therapy	Other: Placebo Placebo
Experimental: Sotatercept plus background PAH therapy Administered at a starting dose of 0.3 mg/kg, with a target dose of 0.7 mg/kg, subcutaneously (SC) every 21 days plus background PAH therapy	Drug: Sotatercept Sotatercept (ACE-011) is a recombinant fusion protein consisting of the extracellular domain of the human activin receptor type IIA linked to the Fc piece of human IgG1 Other Names: ACE-011

Arm

Intervention/Treatment

Placebo Comparator: Placebo plus background PAH therapy

Administered subcutaneously (SC) every 21 days plus background PAH therapy

Other: Placebo

Placebo

Experimental: Sotatercept plus background PAH therapy

Administered at a starting dose of 0.3 mg/kg, with a target dose of 0.7 mg/kg, subcutaneously (SC) every 21 days plus background PAH therapy

Drug: Sotatercept

Sotatercept (ACE-011) is a recombinant fusion protein consisting of the extracellular domain of the human activin receptor type IIA linked to the Fc piece of human IgG1

Other Names:

ACE-011

Outcome Measures

Primary Outcome Measures

Time to Clinical Worsening, defined as the first confirmed morbidity event or death. [From screening to the first clinical worsening event, up to 56 months.]
Clinical worsening events are defined as all-cause death, non-planned PAH-related hospitalization of ≥ 24 hours in duration, atrial septostomy, lung transplant and deterioration in performance in 6-minute walk test from baseline combined with one of the following conditions: worsening of WHO functional class from baseline, signs/symptoms of increased right heart failure, addition of a background PAH therapy or change in the composition of PAH background therapy, including an increase in parenteral prostacyclin of ≥ 10%. All events will be adjudicated by a blinded, independent committee of clinical experts.

Secondary Outcome Measures

Multicomponent improvement endpoint of 6-minute walk distance (6MWD), NT-proBNP and WHO functional class (FC). [From initiation of treatment to Week 24]
Multicomponent improvement endpoint measured by the proportion of participants achieving all of the following at Week 24 relative to baseline Improvement in 6MWD Improvement or maintenance/achievement of NT-proBNP Improvement in WHO FC or maintenance of WHO FC II
Proportion of participants who achieved a low Registry to Evaluate Early and Long Term PAH Disease Management (REVEAL) Lite 2 risk score. [From initiation of treatment to Week 24]
REVEAL Lite 2 risk score in each participant was measured at Week 24 versus baseline.
Proportion of participants who maintain or achieve a low simplified French risk score (FC) [From initiation of treatment to Week 24]
Proportion of participants who maintain or achieve a low risk score at Week 24 versus baseline using the simplified French Risk score calculator was measured.
Change from baseline in NT-proBNP levels. [From initiation of treatment to Week 24]
NT-proBNP was measured at baseline and Week 24.
Proportion of participants who improve in WHO FC or maintain WHO FC II at 24 weeks from baseline. [From initiation of treatment to Week 24]
The severity of an individual's PAH symptoms was graded using WHO FC system at baseline and Week 24.
Change in 6MWD. [From initiation of treatment to Week 24]
6-minute walk test is a clinical exercise test to assess the functional capacity. 6MWD at baseline and Week 24 were measured.
Change in EuroQol - 5 dimensions scale 5 levels (EQ 5D 5L) index score. [From initiation of treatment to Week 24]
EQ 5D 5L index score measures health-related quality of life states in adults. The EQ 5D 5L questionnaire is designed for self-completion and captures information directly from the respondent. EQ 5D 5L index scores at baseline and Week 24 were measured.
Change in Pulmonary Arterial Hypertension Symptoms and Impact (PAH-SYMPACT)® [From initiation of treatment to Week 24]
PAH SYMPACT is a self-rating questionnaire to assess symptoms and their physical and cognitive/emotional impact. The PAH-SYMPACT® questionnaire consists of consists of 16 symptom and 25 impact items. A higher score indicates worse symptoms. Responses in PAH-SYMPACT questionnaire at baseline and Week 24 were recorded.

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

Eligible participants must meet all of the following criteria to be enrolled in the study:

Age ≥ 18 years
Documented diagnostic right heart catheterization (RHC) within 6 months of screening documenting a minimum PVR of ≥ 4 Wood units and pulmonary capillary wedge pressure (PCWP) or left ventricular end-diastolic pressure (LVEDP) of ≤ 15 mmHg, with the diagnosis of WHO PAH Group 1 in any of the following subtypes:

Idiopathic PAH
Heritable PAH
Drug/toxin-induced PAH
PAH associated with connective tissue disease
PAH associated with simple, congenital systemic to pulmonary shunts at least 1 year following repair

Symptomatic PAH classified as WHO FC II or III
REVEAL Lite 2 Risk Score ≥ 6
Diagnosis of PAH within 6 months of screening and on stable doses of a double combination of background PAH therapies for at least 90 days prior to screening. A triple combination of therapies, with stable doses for 90 days, may be allowed per local standard-of-care guidelines, but is restricted to 10% of the study population.
Six-minute walk distance ≥ 150 m repeated twice at screening at least 4 hours apart, but no longer than 1 week apart, and both values are within 15% of each other (calculated from the highest value)
Females of childbearing potential must meet the following criteria:

Have 2 negative urine or serum pregnancy tests as verified by the investigator prior to starting study drug administration; she must agree to ongoing urine or serum pregnancy testing during the course of the study and until 8 weeks after the last dose of the study drug
If sexually active, have used, and agree to use, highly effective contraception without interruption, for at least 28 days prior to starting the investigational product, during the study (including dose interruptions), and for 16 weeks (112 days) after discontinuation of study treatment
Refrain from breastfeeding a child or donating blood, eggs, or ovum for the duration of the study and for at least 16 weeks (112 days) after the last dose of study treatment

Male participants must meet the following criteria:

Agree to use a condom, defined as a male latex condom or nonlatex condom NOT made out of natural (animal) membrane (e.g., polyurethane), during sexual contact with a pregnant female or a female of childbearing potential while participating in the study, during dose interruptions, and for at least 16 weeks (112 days) following investigational product discontinuation, even if he has undergone a successful vasectomy
Refrain from donating blood or sperm for the duration of the study and for 16 weeks (112 days) after the last dose of study treatment

Ability to adhere to study visit schedule and understand and comply with all protocol requirements
Ability to understand and provide written informed consent

Exclusion Criteria:

Participants will be excluded from the study if any of the following criteria are met:

Diagnosis of PAH WHO Groups 2, 3, 4, or 5
Diagnosis of the following PAH Group 1 subtypes: human immunodeficiency virus (HIV)-associated PAH and PAH associated with portal hypertension
Hemoglobin at screening above gender-specific upper limit of normal (ULN), per local laboratory test
Uncontrolled systemic hypertension as evidenced by sitting systolic blood pressure (BP) > 160 mmHg or sitting diastolic BP > 100 mmHg during the Screening Visit after a period of rest
Baseline systolic BP < 90 mmHg at screening
Pregnant or breastfeeding women
Any of the following clinical laboratory values at the Screening Visit:

Estimated glomerular filtration rate < 30 mL/min/m2 (as defined by MDRD equation)
Serum alanine aminotransferase or aspartate aminotransferase levels > 3 × ULN or total bilirubin > 1.5 × ULN
Platelet count < 50,000/mm3 (< 50.0 × 109 /L)

Currently enrolled in or have completed any other investigational product study within 30 days for small molecule drugs or within 5 half-lives for biologics prior to the date of signed informed consent
Known allergic reaction to sotatercept (ACE-011)
History of pneumonectomy
Pulmonary function test values of forced vital capacity < 60% predicted within 1 year prior to the Screening Visit
Stopped receiving any pulmonary hypertension chronic general supportive therapy (e.g., diuretics, oxygen, anticoagulants, and digoxin) within 60 days prior to the Screening Visit
Initiation of an exercise program for cardiopulmonary rehabilitation within 90 days prior to the Screening Visit or planned initiation during the study (participants who are stable in the maintenance phase of a program and who will continue for the duration of the study are eligible)
Untreated obstructive sleep apnea
History of known pericardial constriction
History of restrictive or congestive cardiomyopathy
History of atrial septostomy within 180 days prior to the Screening Visit
1. Electrocardiogram with Fridericia's corrected QT interval > 450 ms (or > 500 ms if right bundle branch abnormality is present) during the Screening Period
Personal or family history of long QT syndrome or sudden cardiac death
Left ventricular ejection fraction < 50% on historical echocardiogram within 1 year prior to the Screening Visit or pulmonary capillary wedge pressure > 15 mmHg as determined by historical RHC within 6 months prior to the Screening Visit
Any current or prior history of symptomatic coronary disease (prior myocardial infarction, percutaneous coronary intervention, coronary artery bypass graft surgery, or cardiac anginal chest pain) in the past 6 months prior to the Screening Visit
Cerebrovascular accident within 3 months prior to the Screening Visit
Acutely decompensated heart failure within 30 days prior to the Screening Visit, as per investigator assessment
Significant (≥ 2+ regurgitation) mitral regurgitation or aortic regurgitation valvular disease
Received intravenous inotropes (e.g., dobutamine, dopamine, norepinephrine, and vasopressin) within 30 days prior to the Screening Visit

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Arizona Pulmonary Specialists ( Site 1010)	Phoenix	Arizona	United States	85013
2	University of Arizona ( Site 1006)	Tucson	Arizona	United States	85724
3	University of California San Diego ( Site 1002)	La Jolla	California	United States	92037
4	University of Colorado Hospital ( Site 1013)	Aurora	Colorado	United States	80045
5	AdventHealth Medical Group Advanced Lung Disease ( Site 1058)	Orlando	Florida	United States	32804
6	University of Iowa Hospital and Clinics ( Site 1050)	Iowa City	Iowa	United States	52242
7	Tufts Medical Center ( Site 1012)	Boston	Massachusetts	United States	02111
8	University of Michigan ( Site 1011)	Ann Arbor	Michigan	United States	48109
9	University of Kansas Medical Center ( Site 1020)	Kansas City	Missouri	United States	66160-7232
10	Washington University School of Medicine ( Site 1022)	Saint Louis	Missouri	United States	63110
11	University of Cincinnati ( Site 1035)	Cincinnati	Ohio	United States	45219
12	Medical University of South Carolina ( Site 1003)	Charleston	South Carolina	United States	29425-8900
13	Centro Medico Dra De Salvo ( Site 1904)	Ciudad Autonoma de Buenos Aires	Buenos Aires	Argentina	C1426ABP
14	Hospital Universitario Austral ( Site 1901)	Pilar	Buenos Aires	Argentina	B1629ODT
15	Instituto de Investigaciones Clinicas Quilmes ( Site 1903)	Quilmes	Buenos Aires	Argentina	B1878GEG
16	Instituto De Enfermedades Respiratorias E Investigacion Medica ( Site 1910)	Villa Vatteone	Buenos Aires	Argentina	B1853AIK
17	Instituto Médico DAMIC ( Site 1909)	Córdoba	Cordoba	Argentina	X5003DCE
18	Instituto Medico Rio Cuarto ( Site 1907)	Rio Cuarto	Cordoba	Argentina	X5800AEV
19	Hospital Provincial del Centenario ( Site 1912)	Rosario	Santa Fe	Argentina	2002
20	Instituto Cardiovascular de Rosario ( Site 1906)	Rosario	Santa Fe	Argentina	S2000DSR
21	Sanatorio Parque ( Site 1905)	Rosario	Santa Fe	Argentina	S2000DSV
22	Sanatorio Allende ( Site 1908)	Cordoba		Argentina	X5021FPQ
23	Hospital Provincial Dr. Jose M. Cullen ( Site 1902)	Santa Fe		Argentina	S3000EOZ
24	Royal Prince Alfred Hospital ( Site 1106)	Camperdown	New South Wales	Australia	2050
25	John Hunter Hospital ( Site 1101)	Newcastle	New South Wales	Australia	2308
26	Prince Charles Hospital ( Site 1104)	Chermside	Queensland	Australia	4032
27	Princess Alexandra Hospital ( Site 1108)	Woolloongabba	Queensland	Australia	4102
28	Royal Adelaide Hospital ( Site 1109)	Adelaide	South Australia	Australia	5000
29	Royal Hobart Hospital ( Site 1107)	Hobart	Tasmania	Australia	7000
30	Fiona Stanley Hospital ( Site 1103)	Murdoch	Western Australia	Australia	6150
31	Ordensklinikum Linz GmbH Elisabethinen ( Site 2002)	Linz	Oberosterreich	Austria	4010
32	Irmandade da Santa Casa de Misericordia de Porto Alegre ( Site 1805)	Porto Alegre	Rio Grande Do Sul	Brazil	90020-090
33	Hospital Sao Paulo ( Site 1806)	São Paulo	Sao Paulo	Brazil	04038-031
34	Instituto do Coracao - HCFMUSP ( Site 1803)	Sao Paulo		Brazil	05403-000
35	St Boniface General Hospital ( Site 2106)	Winnepeg	Manitoba	Canada	R2H 2A6
36	Centro Medico Imbanaco de Cali S.A ( Site 3404)	Santiago de Cali	Valle Del Cauca	Colombia	760042
37	Institut Klinicke a Experimentalni Mediciny ( Site 2202)	Prague	Praha 4	Czechia	140 21
38	Vseobecna fakultni nemocnice v Praze ( Site 2201)	Praha 2		Czechia	128 08
39	Rigshospitalet ( Site 3802)	København Ø	Hovedstaden	Denmark	2100
40	Hopital Louis Pasteur ( Site 1311)	Nice	Alpes-Maritimes	France	06001
41	Hopital Louis Pradel ( Site 1317)	Lyon	Auvergne	France	69003
42	Hopitaux Universitaires de Strasbourg ( Site 1307)	Strasbourg	Bas-Rhin	France	67000
43	CHRU Brest - Hopital Cavale Blanche ( Site 1314)	Brest	Bretagne	France	29200
44	Hopital de la Cote de Nacre - Caen ( Site 1325)	Caen	Calvados	France	14000
45	Hopital Haut Leveque ( Site 1312)	Bordeaux	Gironde	France	33604
46	CHU de Toulouse - Hopital Larrey ( Site 1315)	Toulouse	Haute-Garonne	France	31059
47	C.H.U. de Tours - Hopital Bretonneau ( Site 1310)	Tours	Indre-et-Loire	France	37000
48	CHU de Grenoble - Hopital Michallon ( Site 1303)	Grenoble	Isere	France	38043
49	CHU de Nantes - Hôptal Nord Laennec ( Site 1309)	Nantes	Loire-Atlantique	France	44093
50	Centre Hospitalier Universitaire de Saint-Etienne ( Site 1302)	Saint-Priest-en-Jarez	Loire	France	42055
51	CHU Angers ( Site 1313)	Angers	Maine-et-Loire	France	49933
52	C.H.U. de Nancy. Hopital de Brabois Adultes ( Site 1308)	Vandoeuvre Les Nancy	Meurthe-et-Moselle	France	54500
53	CHU - Hopital de Bicetre ( Site 1304)	Le Kremlin Bicetre	Val-de-Marne	France	94270
54	Thoraxklinik-Heidelberg gGmbH ( Site 1509)	Heidelberg	Baden-Wurttemberg	Germany	69126
55	Krankenhaus Neuwittelsbach ( Site 1510)	Muenchen	Bayern	Germany	80639
56	Medizinische Hochschule Hannover ( Site 1505)	Hannover	Niedersachsen	Germany	30625
57	Universitaetsklinikum Giessen und Marburg GmbH ( Site 1512)	Bad Oeynhausen	Nordrhein-Westfalen	Germany	35392
58	Universitatsklinikum des Saarlandes ( Site 1513)	Homburg	Saarland	Germany	66421
59	Universitaetsklinik und Poliklinik Halle/Saale ( Site 1502)	Halle	Sachsen-Anhalt	Germany	06120
60	Universitaetsklinikum Carl Gustav Carus ( Site 1501)	Dresden	Sachsen	Germany	01307
61	Universitatsklinikum Leipzig ( Site 1508)	Leipzig	Sachsen	Germany	04103
62	DRK Kliniken Berlin Westend ( Site 1507)	Berlin		Germany	14050
63	Onassis Cardiac Surgery Center ( Site 3602)	Athens	Attiki	Greece	176 74
64	Evangelismos General Hospital of Athens ( Site 3605)	Athina	Attiki	Greece	106 76
65	Attikon University General Hospital of Athens ( Site 3604)	Haidari	Attiki	Greece	124 62
66	AHEPA University General Hospital of Thessaloniki ( Site 3601)	Thessaloniki		Greece	546 36
67	Lady Davis Carmel Medical Center ( Site 1705)	Haifa		Israel	34362
68	Hadassah Medical Center ( Site 1711)	Jerusalem		Israel	9112001
69	Sheba Medical Center ( Site 1701)	Ramat Gan		Israel	52621
70	Ospedale S. Giuseppe Multimedica ( Site 2403)	Milan	Lombardia	Italy	20123
71	Azienda Ospedaliera R. N. V. Monaldi ( Site 2407)	Napoli		Italy	80131
72	Azienda Policlinico Umberto I ( Site 2402)	Roma		Italy	00161
73	Gachon University Gil Medical Center ( Site 3103)	Namdong-Gu	Incheon	Korea, Republic of	21565
74	Chonnam National University Hospital ( Site 3105)	Gwangju	Kyonggi-do	Korea, Republic of	61469
75	Samsung Medical Center ( Site 3106)	Seuol	Seoul	Korea, Republic of	06351
76	Seoul National University Hospital ( Site 3102)	Seoul		Korea, Republic of	03080
77	Severance Hospital Yonsei University Health System - PPDS ( Site 3101)	Seoul		Korea, Republic of	03722
78	The Catholic University of Korea St. Mary s Hospital ( Site 3104)	Seoul		Korea, Republic of	06591
79	VU Medisch Centrum ( Site 2601)	Amsterdam	Noord-Holland	Netherlands	1081 HV
80	Erasmus MC ( Site 2604)	Rotterdam	Zuid-Holland	Netherlands	3015 GD
81	Waikato District Health Board ( Site 2702)	Hamilton	Waikato	New Zealand	3204
82	Krakowski Szpital Specjalistyczny im. Jana Pawla II ( Site 2801)	Krakow	Malopolskie	Poland	31-202
83	Europejskie Centrum Zdrowia Otwock Szpital im. Fryderyka Chopina ( Site 2802)	Otwock	Mazowieckie	Poland	05-400
84	Hospital Garcia de Orta ( Site 3501)	Almada	Setubal	Portugal	2801-267
85	Centro Hospitalar E Universitário De Coimbra ( Site 3502)	Coimbra		Portugal	3000-075
86	Hospital Pulido Valente ( Site 3503)	Lisboa		Portugal	1769-001
87	Hospital Universitario Marques de Valdecilla ( Site 1601)	Santander	Cantabria	Spain	39008
88	Hospital Universitario de Son Espases ( Site 1611)	Palma de Mallorca	Islas Baleares	Spain	07120
89	Hospital Universitario Puerta de Hierro (Majadahonda) ( Site 1604)	Majadahonda	Madrid	Spain	28222
90	Hospital Universitari Vall de Hebron ( Site 1605)	Barcelona		Spain	08035
91	Hospital Universitario 12 de Octubre ( Site 1603)	Madrid		Spain	28041
92	Hospital Universitario La Paz ( Site 1610)	Madrid		Spain	28046
93	Hospital Universitario de Salamanca - Complejo Asistencial Universitario de Salamanca ( Site 1608)	Salamanca		Spain	37007
94	Skanes Universitetssjukhus Lund ( Site 3203)	Lund	Skane Lan	Sweden	22185
95	Akademiska Sjukhuset [Uppsala, Sweden] ( Site 3204)	Uppsala	Uppsala Lan	Sweden	751 85
96	Norrlands Universitetssjukhus ( Site 3205)	Umea	Vasterbottens Lan	Sweden	901 85
97	UniversitätsSpital Zürich ( Site 3301)	Zurich		Switzerland	8091
98	Sheffield Teaching Hospital NHS Foundation Trust ( Site 1207)	Sheffield	Derbyshire	United Kingdom	S10 2JF
99	Golden Jubilee National Hospital ( Site 1204)	Glasgow	Glasgow City	United Kingdom	G81 4DY
100	Imperial College Healthcare NHS Trust ( Site 1203)	London	London, City Of	United Kingdom	W12 0HS