PULSAR: A Study of Sotatercept for the Treatment of Pulmonary Arterial Hypertension (PAH)

• Sponsor: Acceleron Pharma Inc. (a wholly owned subsidiary of Merck Sharp and Dohme, a subsidiary of Merck & Co., Inc.) (Industry)
• Overall Status: Completed
• CT.gov ID: NCT03496207
• Collaborator: (none)
• Enrollment: 106
• Locations: 43
• Arms: 3
• Actual Duration (Months): 44.4
• Patients Per Site: 2.5
• Patients Per Site Per Month: 0.1

Study Details

Study Description

Brief Summary

Study A011-09 is designed to assesses the efficacy and safety of sotatercept (ACE-011) relative to placebo in adults with pulmonary arterial hypertension (PAH). Eligible participants will receive study treatment for 6 months in the Placebo-Controlled Treatment Period, and then will be eligible to enroll into an 18- month Extension Period during which all participants will receive sotatercept. All treated patients will be also undergo follow-up period after last study drug treatment.

Condition or Disease	Intervention/Treatment	Phase
Pulmonary Arterial Hypertension	Drug: Placebo; Drug: Sotatercept	Phase 2

Detailed Description

This is a Phase 2, double blind, randomized, placebo-controlled, parallel-group study of sotatercept plus SOC versus placebo plus SOC in participants with PAH of WHO Group 1, functional class II-III.

Participants will be randomly assigned in a 3:3:4 ratio to receive placebo every 21 days, sotatercept 0.3 mg/kg subcutaneously (SC) every 21 days, or sotatercept 0.7 mg/kg SC every 21 days, for a period of 24 weeks in the Placebo-Controlled Treatment Period of the study while on standard of care therapy. Evaluations will include changes in pulmonary vascular resistance (PVR), six-minute-walk distance (6MWD), quality of life questionnaires, echocardiographic parameters, and safety. Participants who have not discontinued early from the Placebo-Controlled Treatment Period and have had their post-Treatment Period PVR assessment will be able to continue into the 18-month Extension Period in which sotatercept-treated participants will receive their latest dose level of sotatercept SC every 21 days and placebo-treated participants willbe re-randomized 1:1 to receive sotatercept 0.3 mg/kg SC every 21 days or sotatercept 0.7 mg/kg SC every 21 days while on standard of care therapy.

Study Design

• Study Type: Interventional
• Actual Enrollment: 106 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: A Phase 2, Double-Blind, Placebo-Controlled, Randomized Study to Compare the Efficacy and Safety of Sotatercept (ACE-011) Versus Placebo When Added to Standard of Care for the Treatment of Pulmonary Arterial Hypertension (PAH)
• Actual Study Start Date: Jun 27, 2018
• Actual Primary Completion Date: Mar 9, 2022
• Actual Study Completion Date: Mar 9, 2022

Arms and Interventions

Arm	Intervention/Treatment
Placebo Comparator: Placebo Placebo SC every 21 days plus SOC for 24 weeks	Drug: Placebo; Placebo
Experimental: Sotatercept 0.3 mg/kg Sotatercept, 0.3 mg/kg SC every 21 days plus SOC for 24 weeks	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
Experimental: Sotatercept 0.7 mg/kg Sotatercept, 0.7 mg/kg SC every 21 days plus SOC for 24 weeks	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

1. Change from baseline in Pulmonary Vascular Resistance (PVR) as measured by right heart catheterization [From initiation of treatment (Study Day 1) to end of placebo-controlled treatment period (Study Day 168)]

2. Extension Period - Change from baseline in PVR at Cycle 25 (or next cycles up to Cycle 33) for the Delayed-Start efficacy analysis [Through study completion up to 24 months.]

3. Extension Period - Change from baseline in PVR at Cycle 25 (or next cycles up to Cycle 33) for the Placebo-Crossed efficacy analysis [Through study completion up to 24 months.]

4. Extension Period - Safety and tolerability assessments based on AEs, clinical laboratory values, and vital signs [Through study completion up to 24 months.]

Secondary Outcome Measures

1. Change from baseline in 6-Minute Walk Distance (6MWD) [From initiation of treatment (Study Day 1) to end of placebo-controlled treatment period (Study Day 168)]

2. Change from baseline in amino-terminal brain natriuretic propeptide (NT-proBNP) [From initiation of treatment (Study Day 1) to end of placebo-controlled treatment period (Study Day 168)]

3. Change from baseline in tricuspid annular plane systolic excursion (TAPSE) by echocardiography (ECHO) [From initiation of treatment (Study Day 1) to end of placebo-controlled treatment period (Study Day 168)]

4. Change from baseline in Cambridge Pulmonary Hypertension Outcome Review (CAMPHOR) patient-reported outcome (PRO) score [From initiation of treatment (Study Day 1) to end of placebo-controlled treatment period (Study Day 168)]

   The CAMPHOR questionnaire contains 65 items in total, 25 relating to symptoms, 15 relating to activities, and 25 relating to Quality of Life (QoL). It is negatively weighted; a higher score indicates worse QoL and greater functional limitation. Symptom and QoL items are both scored out of 25: "yes/true" scores 1 and "no/not true" scores 0. Activity items have three possible responses (score 0-2), giving a score out of 30.

5. Change from baseline in 36-Item Short Form Health Survey (SF-36) patient-reported outcome (PRO) score [From initiation of treatment (Study Day 1) to end of placebo-controlled treatment period (Study Day 168)]

   The SF-36 questionnaire is a 36-item, patient-reported survey of patient health. The questionnaire consists of eight scaled scores, which are the weighted sums of the questions in their section. Each scale is directly transformed into a 0-100 scale on the assumption that each question carries equal weight. The lower the score the more disability. The higher the score the less disability i.e., a score of zero is equivalent to maximum disability and a score of 100 is equivalent to no disability.

6. Clinical worsening (e.g., hospitalizations, change in WHO functional class, and as defined in Section 8.5.4) from C1D1 to C9D1A [From initiation of treatment (Study Day 1) to end of placebo-controlled treatment period (Study Day 168)]

7. Change in WHO functional class at 24 weeks (C9D1A) vs. screening [From initiation of treatment (Study Day 1) to end of placebo-controlled treatment period (Study Day 168)]

8. Safety and tolerability assessments based on adverse events (AEs). [From initiation of treatment (Study Day 1) to end of placebo-controlled treatment period (Study Day 168)]

9. Assessment of vital signs - weight [From initiation of treatment (Study Day 1) to end of placebo-controlled treatment period (Study Day 168)]

10. Assessment of vital signs - blood pressure (systolic/diastolic) [From initiation of treatment (Study Day 1) to end of placebo-controlled treatment period (Study Day 168)]

11. Assessment of vital signs - respiratory rate [From initiation of treatment (Study Day 1) to end of placebo-controlled treatment period (Study Day 168)]

12. Assessment of vital signs - EKG (QTcF interval) [From initiation of treatment (Study Day 1) to end of placebo-controlled treatment period (Study Day 168)]

13. Assessment of PK parameter(s) Maximum Plasma Concentration [Cmax] [From initiation of treatment (Study Day 1) to end of placebo-controlled treatment period (Study Day 168)]

14. Extension Period - Change from baseline in 6MWD at Cycle 25 (or next cycles up to Cycle 33) for the Delayed-Start efficacy analysis [From initiation of treatment (Study Day 1) to end of placebo-controlled treatment period (Study Day 168)]

15. Extension Period - Change from baseline in 6MWD at Cycle 25 (or next cycles up to Cycle 33) for the Placebo-Crossed efficacy analysis [From initiation of treatment (Study Day 1) to end of placebo-controlled treatment period (Study Day 168)]

16. Extension Period - Change from baseline in WHO FC at Cycle 25 (or next cycles up to Cycle 33) for the Delayed-Start efficacy analysis [From initiation of treatment (Study Day 1) to end of placebo-controlled treatment period (Study Day 168)]

17. Extension Period - Change from baseline in WHO FC at Cycle 25 (or next cycles up to Cycle 33) for the Placebo-Crossed efficacy analysis [From initiation of treatment (Study Day 1) to end of placebo-controlled treatment period (Study Day 168)]

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

1. Age ≥ 18 years

2. Documented diagnostic right heart catheterization (RHC) at any time prior to Screening confirming diagnosis of WHO diagnostic pulmonary hypertension Group I: PAH in any of the following subtypes:

1. Idiopathic ii. Heritable PAH iii. Drug- or toxin-induced PAH iv. PAH associated with connective tissue disease v. PAH associated with simple, congenital systemic-to-pulmonary shunts at least 1 year following shunt repair

1. Symptomatic pulmonary hypertension classified as WHO functional class II or III

2. Screening RHC documenting a minimum PVR of ≥ 400 dyn·sec/cm5 (5 Wood units)

3. Pulmonary function tests (PFTs) within 6 months prior to Screening as follows:

4. Total lung capacity (TLC) > 70% predicted; or if between 60 to70% predicted, or not possible to be determined, confirmatory high-resolution computed tomography (CT) indicating no more than mild interstitial lung disease (ILD), per investigator interpretation, or

5. Forced expiratory volume (first second) (FEV1)/ forced vital capacity (FVC) > 70% predicted

6. Ventilation-perfusion (VQ) scan (or, if unavailable a negative CT pulmonary angiogram [CTPA] result, or pulmonary angiography result), any time prior to Screening Visit or conducted during the Screening Period, with normal or low probability result),

7. No contraindication per investigator for RHC during the study

8. 6MWD ≥ 150 and ≤ 550 meters repeated twice at Screening and both values within 15% of each other, calculated from the highest value

9. PAH therapy at stable (per investigator) dose levels of SOC therapies

Exclusion Criteria:

1. Stopped receiving any pulmonary hypertension chronic general supportive therapy (e.g, diuretics, oxygen, anticoagulants, digoxin) within 60 days prior to study visit C1D1

2. Received intravenous inotropes (e.g., dobutamine, dopamine, norepinephrine, vasopressin) within 30 days prior to study visit C1D1

3. History of atrial septostomy within 180 days prior to Screening

4. History of more than mild obstructive sleep apnea that is untreated

5. Known history of portal hypertension or chronic liver disease, including hepatitis B and/or hepatitis C (with evidence of recent infection and/or active virus replication), defined as mild to severe hepatic impairment (Child-Pugh Class A-C)

6. History of human immunodeficiency virus infection-associated PAH

7. Prior exposure to sotatercept (ACE-011) or luspatercept (ACE-536)

8. Initiation of an exercise program for cardiopulmonary rehabilitation within 90 days prior to C1D1 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).

9. Uncontrolled systemic hypertension as evidenced by sitting systolic blood pressure (BP) > 160 mm Hg or sitting diastolic blood pressure > 100 mm Hg during Screening Visit after a period of rest

10. Systolic BP < 90 mmHg during Screening or at baseline

11. History of known pericardial constriction

12. Electrocardiogram (ECG) with Fridericia's corrected QT interval (QTcF) > 480 msec during Screening Period or C1D1

13. Personal or family history of long QTc syndrome or sudden cardiac death

14. Cerebrovascular accident within 3 months of C1D1

15. History of restrictive or congestive cardiomyopathy

16. Left ventricular ejection fraction (LVEF) < 45% on historical echocardiogram (ECHO) within 6 months prior to Screening Period (or done as a part of the Screening Period) or pulmonary capillary wedge pressure (PCWP) > 15 mmHg as determined in the Screening Period RHC.

17. 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)

18. Acutely decompensated heart failure within 30 days prior to study visit C1D1, as per investigator assessment

19. Significant (≥ 2+ regurgitation) mitral regurgitation (MR) or aortic regurgitation (AR) valvular disease

20. Any of the following clinical laboratory values during the Screening Period prior to

C1D1:

1. Baseline Hgb > 16.0 g/dL

2. Serum alanine aminotransferase or aspartate aminotransferase levels > 3X upper limit of normal (ULN) or total bilirubin > 1.5X ULN within 28 days of C1D1

3. Estimated glomerular filtration rate < 30 ml/min/1.73m2 (4-variable Modification of Diet in Renal Disease equation) within 28 days of C1D1 or required renal replacement therapy within 90 days

4. WBC count < 4000/mm3

5. Platelets < 100,000/μL

6. Absolute neutrophil count < 1500/mm3

7. History of opportunistic infection (e.g., invasive candidiasis or pneumocystis pneumonia) within 6 months prior to Screening; serious local infection (e.g., cellulitis, abscess) or systemic infection (e.g., septicemia) within 3 months prior to Screening

8. History of severe allergic or anaphylactic reaction or hypersensitivity to recombinant proteins or excipients in the investigational product

9. Major surgery within 8 weeks prior to C1D1. Participants must have completely recovered from any previous surgery prior to C1D1.

10. Prior heart or heart-lung transplants or life expectancy of < 12 month

11. Pregnant or breastfeeding females

12. If on corticosteroids, and at any time in the last 30 days prior to the Screening Period: have been receiving doses of > 20 mg/day of prednisone (or equivalent) or on a new or changing dose of ≤ 20 mg/day; only participants receiving stable doses of ≤ 20 mg prednisone (or equivalent) in last 30 days prior to the Screening Period permitted in the study

13. History of active malignancy, with the exception of fully excised or treated basal cell carcinoma, cervical carcinoma in-situ, or ≤ 2 squamous cell carcinomas of the skin

14. History of clinically significant (as determined by the investigator) non-PAH related cardiac, endocrine, hematologic, hepatic, (auto)immune, metabolic, urologic, pulmonary, neurologic, neuromuscular, dermatologic, psychiatric, renal, and/or another disease that may limit participation in the study. Autoimmune diseases are excluded with the exception of those related to PAH etiologies included in this study.

15. Participation in another clinical trial involving intervention with another investigational drug, approved therapy for investigational use, or investigational device within 4 weeks prior to C1D1, or if the half-life of the previous product is known, within 5 times the half-life prior to C1D1, whichever is longer

16. Weight > 140 kg at Screening

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Pulmonary Associates, PA	Phoenix	Arizona	United States	85006
2	Arizona Pulmonary Specialists	Phoenix	Arizona	United States	85012
3	Banner-University Medical Center Phoenix	Phoenix	Arizona	United States	85381
4	University of Arizona	Tucson	Arizona	United States	85724
5	University of California, San Francisco Medical Center	San Francisco	California	United States	94143
6	University of Colorado Hospital	Aurora	Colorado	United States	80045
7	UF Health Shands Hospital	Gainesville	Florida	United States	32610
8	University of Kansas Medical Center	Kansas City	Kansas	United States	66160
9	University of Michigan	Ann Arbor	Michigan	United States	48109
10	Lindner Clinical Trial Center	Cincinnati	Ohio	United States	45129
11	Medical University of South Carolina	Charleston	South Carolina	United States	29425
12	Houston Methodist Hospital	Houston	Texas	United States	77030
13	St. Vincent's Hospital Sydney	Darlinghurst	New South Wales	Australia	2010
14	Westmead Hospital	Westmead	New South Wales	Australia	2145
15	John Hunter Hospital	New Lambton	New South Whales	Australia	2305
16	Prince Charles Hospital	Chermside	Queensland	Australia	4032
17	Hospital Madre Teresa	Belo Horizonte	Minas Gerais	Brazil	30430
18	Irmandade Da Santa Casa de Misericordia de Porto Alegre	Porto Alegre	Riogrande Do Sul	Brazil	90035
19	Hospital Dia do Pulmão	Blumenau	Santa Catarina	Brazil	89010
20	Instituto do Coracao - HCFMUSP	Cerqueira César		Brazil	05403-900
21	Hospital Sao Lucas da PUCRS	Jardim Botânico		Brazil	05403-900
22	Hospital São Paulo	Sao Paulo		Brazil	04037
23	Hôpital Arnaud de Villeneuve	Montpellier	Hérault	France	34295
24	CHU Michallon	La Tronche		France	38700
25	Centre Hospitalier Universitaire de Bicêtre	Le Kremlin-Bicêtre		France	94275
26	Centre Hospitalier Universitaire de Saint Etienne	Saint-Étienne		France	42055
27	Medizinische Hochschule Hannover	Hannover	Niedersachsen	Germany	30625
28	Universitatsklinikum Halle (Saale)	Halle	Sachsen-Anhalt	Germany	06120
29	Universitatsklinikum Leipzig	Leipzig	Sachsen	Germany	04103
30	Universitätsklinikum Carl Gustav Carus an der TU Dresden	Dresden		Germany	01307
31	Barzilai Medical Center	Ashkelon		Israel	78278
32	Lady Davis Carmel Medical Center	Haifa		Israel	34362
33	Meir Medical Center	Kefar Sava		Israel	4428100
34	Rabin Medical Center - PPDS	Petach-Tikva		Israel	49100
35	Chaim Sheba Medical Center	Ramat Gan		Israel	52621
36	Hospital Universitario Marques de Valdecilla	Santander	Cantabria	Spain	39008
37	Hospital Universitario Puerta de Hierro-Majadahonda	Majadahonda	Madrid	Spain	28222
38	Hospital Universitario Vall d'Hebron - PPDS	Barcelona		Spain	08035
39	Hospital Clinic de Barcelona	Barcelona		Spain	08036
40	Hospital Universitario 12 de Octubre	Madrid		Spain	28041
41	Golden Jubilee National Hospital - PPDS	Clydebank		United Kingdom	G81 4DY
42	Royal Free London NHS Foundation Trust	London		United Kingdom	NW32QG
43	Imperial College Healthcare NHS Trust	London		United Kingdom	W2 1NY

Sponsors and Collaborators

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

Investigators

None specified.

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Acceleron Pharma Inc. (a wholly owned subsidiary of Merck Sharp and Dohme, a subsidiary of Merck & Co., Inc.)
• ClinicalTrials.gov Identifier: NCT03496207
• Other Study ID Numbers: A011-09; 2017-004738-27
• First Posted: Apr 12, 2018
• Last Update Posted: May 4, 2022
• Last Verified: May 1, 2022

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Keywords provided by Acceleron Pharma Inc. (a wholly owned subsidiary of Merck Sharp and Dohme, a subsidiary of Merck & Co., Inc.): PAH
• Additional relevant MeSH terms: Pulmonary Arterial Hypertension; Familial Primary Pulmonary Hypertension; Hypertension

Study Results

No Results Posted as of May 4, 2022