A Study of Sotatercept for the Treatment of Pulmonary Arterial Hypertension

Pulmonary Arterial Hypertension Clinical Trial

— SPECTRA  

Official title:

A Phase 2a Single-Arm, Open-Label, Multicenter Exploratory Study to Assess the Effects of Sotatercept (ACE-011) for the Treatment of Pulmonary Arterial Hypertension

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT03738150
• Other study ID #: A011-10
• Secondary ID: 7962-002
• Status: Completed
• Phase: Phase 2
• Start date: April 19, 2019
• Est. completion date: March 22, 2022

Study information

• Verified date: January 2023
• Source: Acceleron Pharma Inc. (a wholly owned subsidiary of Merck Sharp and Dohme, a subsidiary of Merck & Co., Inc.)
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

This study evaluates the effect of sotatercept (ACE-011) in adults with pulmonary arterial hypertension (PAH). Each eligible participant will receive standard of care (SOC) plus sotatercept (ACE-011) for a 24-week treatment period, followed by an 18-month extension period, and an 8-week follow-up period.

Description:

This is a Phase 2a, single-arm, open-label, multicenter exploratory study to determine the effects of sotatercept plus SOC in adults with WHO functional class III PAH.

All eligible participants will receive SOC plus sotatercept at a starting dose level of 0.3 mg/kg by subcutaneous (SC) injection for Cycle 1 and escalating to 0.7 mg/kg at Cycle 2 for the remainder of the treatment period. Participants will be required to attend clinic visits once every three weeks for the 24-week treatment period and once every three weeks for the 18-month extension period to perform one or more protocol specified evaluations. Evaluations include hemodynamic measures collected during right heart catheterization (RHC) with invasive cardiopulmonary exercise test (iCPET), and cardiac magnetic resonance imaging (MR), 6-minute walk distance (6MWD), pharmacokinetic parameters, pharmacodynamic parameters, anti-drug antibody testing, and adverse events.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 21
• Est. completion date: March 22, 2022
• Est. primary completion date: December 21, 2021
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

1. Age = 18 years

2. Documented findings on RHC at any time prior to Screening consistent with a diagnosis of World Health Organization (WHO) pulmonary hypertension Group 1: PAH of any of the following subtypes:

• Idiopathic PAH

• Heritable PAH

• Drug- or toxin-induced PAH

• PAH associated with connective tissue disease

• PAH associated with simple, congenital systemic-to-pulmonary shunts at least 1 year following shunt repair

3. Symptomatic pulmonary hypertension classified as WHO functional class III

4. Screening RHC documenting a minimum PVR of = 4 Wood units

5. Pulmonary function tests within 6 months prior to Screening as follows:

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

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

3. For subjects with a history of lobectomy or pneumonectomy, and for whom there are no population-based normalization methods, assessment based on residual lung volume will be permitted to assess eligibility.

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

7. 6MWD = 100 and = 550 meters repeated twice during Screening Period and both values within 15% of each other, calculated from the highest value

8. Combination PAH therapy at stable (per investigator) dose levels for at least 90 days prior to Cycle 1 Day 1 (C1D1)

Exclusion Criteria:

Participants will be excluded from the study if they meet any of the following criteria:

1. Started or stopped receiving any general supportive therapy for pulmonary hypertension (e.g., diuretics, oxygen, anticoagulants, digoxin) within 60 days prior to C1D1 (Cycle 1 Day 1)

2. Received intravenous inotropes (e.g., dobutamine, dopamine, norepinephrine, vasopressin) within 30 days prior to 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. History of portal hypertension or chronic liver disease, defined as mild to severe hepatic impairment (Child-Pugh Classes A to C)

6. History of human immunodeficiency virus infection-associated PAH

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

8. Uncontrolled systemic hypertension as evidenced by sitting systolic BP > 160 mm Hg or sitting diastolic BP > 100 mm Hg during Screening after a period of rest

9. Systolic BP < 90 mm Hg during Screening or at baseline

10. History of known pericardial constriction

11. Electrocardiogram (ECG) with QTcF > 480 msec during Screening or C1D1

12. History of personal or family history of long QTc syndrome or sudden cardiac death

13. History of restrictive or constrictive cardiomyopathy

14. Left ventricular ejection fraction < 45% on echocardiogram performed within 6 months of Screening OR pulmonary capillary wedge pressure (PCWP) > 15 mm Hg on RHC during baseline evaluation

15. Any current symptomatic coronary disease (myocardial infarction, percutaneous coronary intervention, coronary artery bypass graft surgery, or cardiac anginal chest pain in the past 6 months prior to Screening)

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

17. Significant (= 2+ regurgitation) mitral regurgitation or aortic regurgitation valvular disease

Related Conditions & MeSH terms

• Familial Primary Pulmonary Hypertension
• Hypertension
• Pulmonary Arterial Hypertension

Intervention

Biological:
• Sotatercept
Sotatercept injection

Other:
• SOC
SOC therapy refers to combination therapy consisting of drugs from two or more of the following drug classes: an endothelin-receptor antagonist (ERA), a phosphodiesterase 5 (PDE5) inhibitor, a soluble guanylate cyclase stimulator, and/or a prostacyclin analogue or receptor agonist.

Locations

Country	Name	City	State
United States	Brigham and Women's Hospital	Boston	Massachusetts
United States	University of Pittsburgh Medical Center	Pittsburgh	Pennsylvania
United States	Mayo Clinic	Rochester	Minnesota
United States	The University of Arizona	Tucson	Arizona

Sponsors (1)

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

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Change From Baseline in Peak Oxygen Uptake (VO2 Max) at 24 Weeks	Each participant's VO2 max was measured by an invasive cardiopulmonary exercise test (iCPET) at baseline and at 24 weeks.	Baseline and 24 weeks
Secondary	Change From Baseline in Right Ventricular Stroke Volume (RV SV) at 24 Weeks	Each participant's RV SV was measured by cardiac MRI at baseline and at 24 weeks.	Baseline and 24 weeks
Secondary	Change From Baseline in Right Ventricular End-Systolic Volume (RV ESV) at 24 Weeks	Each participant's RV ESV was measured by cardiac MR imaging at baseline and at 24 weeks.	Baseline and 24 weeks
Secondary	Change From Baseline in Right Ventricular End-Diastolic Volume (RV EDV) at 24 Weeks	Each participant's RV EDV was measured by cardiac MR imaging at baseline and at 24 weeks.	Baseline and 24 weeks
Secondary	Percent Change From Baseline in Right Ventricular Ejection Fraction (RV EF) at 24 Weeks	Each participant's RV EF was measured by cardiac MR imaging at baseline and at 24 weeks.	Baseline and 24 Weeks
Secondary	Change From Baseline in Right Ventricular Stroke Volume Index (RV SVI) at 24 Weeks	Each participant's RV SVI was measured by cardiac MR imaging at baseline and at 24 weeks.	Baseline and 24 weeks
Secondary	Change From Baseline in Right Ventricular (RV) Mass at 24 Weeks	Each participant's RV mass was measured by cardiac MR imaging at baseline and at 24 weeks.	Baseline and 24 weeks
Secondary	Change From Baseline in Ventilatory Efficiency (VE/VCO2 Slope) at 24 Weeks	VE/VCO2 slope refers to the slope of the regression line of Minute Ventilation (VE) in liters/minute in the Y-axis and corresponding carbon dioxide production per minute (VCO2) in liters/minute in the X-axis plotted with multiple measurements taken during exercise. Each participant's VE/VCO2 slope at peak exercise was measured by an iCPET at baseline and at 24 weeks.	Baseline and 24 weeks
Secondary	Change From Baseline in Cardiac Index at 24 Weeks	Each participant's cardiac index at peak exercise was measured by iCPET at baseline and at 24 weeks.	Baseline and 24 weeks
Secondary	Change From Baseline in Mean Pulmonary Arterial Pressure at 24 Weeks	Each participant's pulmonary arterial pressure at peak exercise was measured by iCPET at baseline and at 24 weeks.	Baseline and 24 weeks
Secondary	Change From Baseline in Arteriovenous O2 Content Difference (Ca-vO2) at 24 Weeks	Each participant's Ca-vO2 at peak exercise was measured by iCPET at baseline and at 24 weeks.	Baseline and 24 weeks
Secondary	Change From Baseline in Pulmonary Vascular Resistance (PVR) at 24 Weeks	Each participant's PVR, at resting supine, was measured by right heart catheterization (RHC) at baseline and at 24 weeks.	Baseline and 24 weeks
Secondary	Change From Baseline in 6-Minute Walk Distance (6MWD) at 24 Weeks	6MWD is measured by an exercise test known as 6MWT that assesses aerobic capacity and endurance. It measures the distance covered over a time of 6 minutes and is used as an outcome measure by which to compare changes in performance capacity. Each participant's 6MWD was measured at baseline and at 24 weeks. An increase in the distance walked during the 6MWT indicates improvement in basic mobility.	Baseline and 24 weeks
Secondary	Change From Baseline in Concentration of Amino-Terminal Brain Natriuretic Propeptide (NT-proBNP) at 24 Weeks	Each participant's laboratory biomarkers N-terminal prohormone brain-type natriuretic peptide (NT-proBNP) or brain-type natriuretic peptide (BNP) were measured at baseline and at 24 weeks.	Baseline and 24 Weeks
Secondary	Change From Baseline in WHO (World Health Organization) Functional Class at 24 Weeks	The World Health Organization (WHO) functional class describes how severe a person's pulmonary hypertension symptoms are. There are four different classes - I is the mildest and IV the most severe form of pulmonary hypertension.	Baseline and 24 Weeks
Secondary	Number of Participants With One or More Adverse Events (AEs)	An AE is any untoward medical occurrence in a study participant administered a pharmaceutical product that does not necessarily have to have a causal relationship with this treatment. An AE can therefore be any unfavorable and unintended sign, symptom, or disease temporally associated with the use of a medicinal product, whether or not related to the medicinal product.	Up to 24 weeks
Secondary	Number of Participants Who Experienced One or More Events Indicative of Clinical Worsening of Pulmonary Arterial Hypertension (PAH)	Events that indicate clinical worsening of PAH include death, need for and/or worsening-related listing for lung and/or heart transplant, need to initiate an approved PAH SOC rescue therapy, PAH-specific hospitalization, or functional deterioration (worsened WHO Functional Class AND 15% decrease in 6MWD).	Up to 102 weeks
Secondary	Observed Trough Concentration (Ctrough) of Sotatercept at Cycle 9	Ctrough is the plasma concentration of a drug prior to administration.	Day 1 of Cycle 9 (Each cycle was 21 days.)
Secondary	Maximum Plasma Concentration (Cmax) of Sotatercept at Cycle 9	Cmax is a measure of the maximum amount of drug in the plasma after the dose is given. PopPK modeling approach was used to build a population PK model that captures the totality of the observed data from Cycles 1 to 9. The Cmax parameter is derived from this preliminary popPK modeling.	Day 1 of each 21-day cycle: Cycles 1-9
Secondary	Minimum Plasma Concentration (Cmin) of Sotatercept at Cycle 9	Cmin is a measure of the minimum amount of drug in the plasma after the dose is given. PopPK modeling approach was used to build a population PK model that captures the totality of the observed data from Cycles 1 to 9. The Cmin parameter is derived from this preliminary popPK modeling.	Day 1 of each 21-day cycle: Cycles 1-9
Secondary	Average Concentration (Cavg) of Sotatercept at Cycle 9	Cavg is calculated by area under the plasma concentration versus dosing interval time curve at steady-state divided by the dosing interval. PopPK modeling approach was used to build a population PK model that captures the totality of the observed data from Cycles 1 to 9. The Cavg parameter is derived from this preliminary popPK modeling.	Day 1 of each 21-day cycle: Cycles 1-9
Secondary	Area Under the Concentration-Time Curve From 0 to T (AUC0-T) of Sotatercept at Cycle 9	AUC0-T (area under the plasma concentration versus time curve from time zero after a dose is given to a period of one 21-day cycle) is a measure of the mean concentration levels of a drug in the plasma at steady state. PopPK modeling approach was used to build a population PK model that captures the totality of the observed data from Cycles 1 to 9. The AUC0-T parameter is derived from this preliminary popPK modeling.	Day 1 of each 21-day cycle: Cycles 1-9
Secondary	Apparent Terminal Half-life (t1/2 ) of Sotatercept at Cycle 9	t1/2 is the elimination half-life of study drug: the time it takes for half of the study drug in the blood plasma to dissipate. PopPK modeling approach was used to build a population PK model that captures the totality of the observed data from Cycles 1 to 9. The t1/2 parameter is derived from this preliminary popPK modeling.	Day 1 of each 21-day cycle: Cycles 1-9
Secondary	Apparent Serum Clearance (CL) of Sotatercept at Cycle 9	Apparent serum CL is a measure of the rate at which a drug is metabolized or eliminated by normal biological processes. PopPK modeling approach was used to build a population PK model that captures the totality of the observed data from Cycles 1 to 9. The apparent serum CL parameter is derived from this preliminary popPK modeling.	Day 1 of each 21-day cycle: Cycles 1-9
Secondary	Apparent Volume of Distribution (Vz/F) of Sotatercept at Cycle 9	Vz/F is defined as the theoretical volume in which the total amount of drug would need to be uniformly distributed to produce the desired plasma concentration of a drug. PopPK modeling approach was used to build a population PK model that captures the totality of the observed data from Cycles 1 to 9. The Vz/F parameter is derived from this preliminary popPK modeling.	Day 1 of each 21-day cycle: Cycles 1-9
Secondary	Absorption Rate Constant (Ka) of Sotatercept at Cycle 9	Ka is the proportionality constant that relates the rate of drug absorbed into the body. Ka is a value used to describe the rate at which a drug enters into the system. It is expressed in units of time. PopPK modeling approach was used to build a population PK model that captures the totality of the observed data from Cycles 1 to 9. The Ka parameter is derived from this preliminary popPK modeling.	Day 1 of each 21-day cycle: Cycles 1-9