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…
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Source
Brief title
Condition
- Vascular hypertensive disorders
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
The primary efficacy endpoint is TTCW, defined as the time from randomization
to the first confirmed morbidity event or death. The events that will comprise
this endpoint include the following:
• All-cause death
• Non-planned PAH-related hospitalization of >= 24 hours in duration
• Atrial septostomy
• Lung transplant
• Deterioration in performance in exercise testing due to PAH, defined as a
decrease in 6MWD from baseline (average of screening) on 2 consecutive tests
(which must be at least 4 hours apart) and at least 1 of the following:
- Worsening of WHO FC from baseline
- Signs/symptoms of increased right heart failure
- Addition of a background PAH therapy or change in the background PAH therapy
delivery route to parenteral
All events will be adjudicated by a blinded, independent committee of clinical
experts.
Secondary outcome
The 9 secondary endpoints are ranked as follows:
1. Multicomponent improvement endpoint measured by the proportion of
participants achieving all of the following at Week 24 relative to baseline:
• Improvement in 6MWD (increase >= 30 meters [m])
• Improvement in NT-proBNP (decrease in NT-proBNP >= 30%) or
maintenance/achievement of NT-proBNP level < 300 ng/L
• Improvement in WHO FC or maintenance of WHO FC II
2. Proportion of participants who maintain or achieve a low-risk category of
REVEAL Lite 2 risk score at Week 24 versus baseline
3. Proportion of participants who maintain or achieve a low risk score at Week
24 versus baseline using the simplified French Risk score calculator
4. Change from baseline in NT-proBNP levels at Week 24
5. Proportion of participants who improve in WHO FC or maintain WHO FC II at 24
weeks from baseline
6. Change from baseline in 6MWD at Week 24
7. Change from baseline in the Physical Impacts domain score of Pulmonary
Arterial Hypertension-Symptoms and Impact (PAH SYMPACT®) at Week 24
8. Change from baseline in the Cardiopulmonary Symptoms domain score of
PAH-SYMPACT® at Week 24
9. Change from baseline in the Cognitive/Emotional Impacts domain score of
PAH-SYMPACT® at Week 24
Background summary
Pulmonary Arterial Hypertension is a progressive, fatal disease that causes
marked limitations in physical activity and quality of life, even when treated
with approved therapies. This Phase 3 study is supported by data from the
PULSAR study (Phase 2, NCT03496207) and the STELLAR study (Phase 3,
NCT04576988). In PULSAR, participants taking any approved single or combination
therapy for PAH were randomized to receive sotatercept (ACE-011, MK-7962) or
placebo for 24 weeks. PULSAR demonstrated a statistically significant
improvement in its primary endpoint, pulmonary vascular resistance (PVR).
Additionally, improvement was observed in 6-minute walk distance (6MWD),
N-terminal prohormone B-type natriuretic peptide (NT-proBNP) levels, and other
endpoints. In STELLAR, participants taking single or combination PAH therapy
were randomized to receive sotatercept or placebo for 24 weeks. STELLAR
demonstrated a statistically significant and clinically meaningful improvement
in its primary endpoint, 6MWD, and achieved statistical significance in 8 of 9
secondary efficacy outcome measures, including improvements in PVR and the
World Health Organization (WHO) functional class (FC) [Hoeper, M. M., et al
2023].
Study objective
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.
Study design
Phase 3, randomized, double-blind, placebo-controlled, multicenter,
parallel-group study
Intervention
Each eligible participant will be randomized in a 1:1 ratio to 1 of the
following 2 treatment arms during the DBPC Treatment Period:
• Arm 1: Placebo administered subcutaneously (SC) every 21 days plus background
PAH therapy
• Arm 2: Sotatercept at a starting dose of 0.3 mg/kg, with a target dose of 0.7
mg/kg, SC every 21 days plus background PAH therapy
Study burden and risks
The study treatment may cause side effects. Side effects can be mild to severe
and they can vary from person to person.
Listed below are side effects reported in participants of previous PAH studies
:
• Headache
• Diarrhea
• Nosebleeds
• Feeling tired
• Dizziness
• Telangiectasia (small red, threadlike patterns of blood vessels on the skin)
• Increase in red blood cells, hemoglobin, and hematocrit (proportion of red
blood cells
in the bloodstream)
• Low level of platelets (blood cells involved in forming blood clots)
• Increased blood pressure (hypertension)
• Hot flush
• Rash
• Decrease in levels of blood potassium
• Pain in extremity
• Swelling in the limbs
• Nausea
• Urinary tract infection
• Nasal congestion
• Feeling of physical weakness or less strength
• Sensation of numbness or tingling of the skin
• Muscle spasms
• Back pain
• Fever
• Vomiting
• Dehydration
There are also certain risks associated with the use of sotatercept:
In previous sotatercept studies in patients with PAH, there have been reports
of increases in red blood cells, hemoglobin (a molecule in your blood that
carries oxygen), and hematocrit (a way to measure amount of red blood cells) as
well as increases in blood pressure which might require treatment. An increase
in red blood cells may lead to associated events like headache, high blood
pressure, blood clotting in your blood vessels, lack of blood flow and oxygen
to your brain, damage to organs and eyes, and death.
In previous sotatercept studies in patients with PAH, some participants had a
decrease in platelet count. This change may pose a potential risk for bruising
and bleeding. You will be tested throughout the study to monitor for platelet
counts.
As with any drug, it is possible that participants have allergic reactions.
Sotatercept is a protein and therefore your body may make antibodies to
sotatercept.
Right Heart Catheterization
While uncommon, the risks of RHC include air leak in the lungs and perforation
of major vessels with possible bleeding or irregular heartbeat. Participants
will receive radiation exposure as images are taken of the heart and blood
vessels.
Radiation Exposures:
For RHC tests we use X-rays. In this study, participants will receive
approximately 7.5 mSv of radiation in total if they require a RHC.
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Listed location countries
Age
Inclusion criteria
1. Age >= 18 years
2. Documented diagnostic right heart catheterization (RHC) within 12 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 CTD
• PAH associated with simple, congenital systemic to pulmonary shunts at least
1 year following repair
3. Symptomatic PAH classified as WHO FC II or III
4. Either REVEAL Lite 2 risk score >= 6 or COMPERA 2.0 risk score >= 2
(intermediate-low-risk or above)
5. Diagnosis of PAH within 12 months of screening and on stable doses of a
double or triple combination of background PAH therapies and diuretics (if any)
for at least 90 days prior to screening. Background PAH therapy and diuretics
are further defined in Section 7.2.
6. 6MWD >= 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)
7. Females of childbearing potential (as defined in Appendix 4) must meet the
following criteria:
• Have 2 negative urine or serum pregnancy tests as verified by the
investigator during the Screening Period;
• Agree to ongoing pregnancy testing (either urine or serum) during the course
of the study and until 8 weeks after the last dose of the study drug
• If sexually active with a male partner:
- Used highly effective contraception without interruption for at least 28 days
prior to starting the investigational product AND
- Agreed to use the same highly effective contraception in combination with a
barrier method 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
8. 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
9. Ability to adhere to study visit schedule and understand and comply with all
protocol requirements
10. Ability to understand and provide documented informed consent
Exclusion criteria
1. Diagnosis of pulmonary hypertension (PH) WHO Groups 2, 3, 4, or 5
2. Diagnosis of the following PAH Group 1 subtypes: human immunodeficiency
virus (HIV)-associated PAH, PAH associated with portal hypertension,
schistosomiasis-associated PAH, pulmonary veno occlusive disease and pulmonary
capillary hemangiomatosis
3. Hgb at screening above gender-specific upper limit of normal (ULN), per
local laboratory test
4. Uncontrolled systemic hypertension as evidenced by sitting systolic blood
pressure (BP) > 180 mmHg or sitting diastolic BP > 110 mmHg during the
Screening Visit after a period of rest
5. Baseline systolic BP < 90 mmHg at screening
6. Pregnant or breastfeeding women
7. Any of the following clinical laboratory values at the Screening Visit:
• Estimated glomerular filtration rate (eGFR) < 30 mL/min/1.73 m2 (as defined
by MDRD equation)
• Serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), or
total bilirubin levels > 3 × ULN (For United Kingdom [UK], refer to the
specific requirement in Appendix 6)
• Platelet count < 50,000/mm3 (< 50.0 × 109/L)
8. Currently enrolled in or have completed any other investigational product
study within 30 days for small molecule drugs or within 5 half-lives for
investigational biologics prior to the date of documented informed consent
9. Known allergic reaction to sotatercept (ACE-011), its excipients, or
luspatercept
10. History of pneumonectomy
11. Pulmonary function test values of forced vital capacity < 60% predicted
within 1 year prior to the Screening Visit
12. Stopped receiving any PH chronic general supportive therapy (e.g.,
diuretics, oxygen, anticoagulants, and digoxin) within 60 days prior to the
Screening Visit
13. 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)
14. Untreated more than mild obstructive sleep apnea
15. History of known pericardial constriction
16. History of restrictive cardiomyopathy
17. History of atrial septostomy within 180 days prior to the Screening Visit
18. Electrocardiogram (ECG) with Fridericia*s corrected QT interval > 500 ms
during the Screening Period (For UK and South Korea, refer to the specific
requirements in Appendix 6).
19. Personal or family history of long QT syndrome or sudden cardiac death
20. Left ventricular ejection fraction < 50% documented by a historical
echocardiograph (ECHO) or cardiac magnetic resonance imaging (MRI) within the
last 12 months prior to screening (if there is more than 1 assessment of left
ventricular ejection fraction (LVEF), the value from the most recent
measurement should be used in assessing eligibility)
21. Coronary artery disease (myocardial infarction, percutaneous coronary
intervention, coronary artery bypass graft surgery, or cardiac anginal chest
pain) within 6 months prior to the Screening Visit
22. Cerebrovascular accident within 3 months prior to the Screening Visit
23. Acutely decompensated heart failure within 30 days prior to the Screening
Visit, as per investigator assessment
24. Significant (>= 2+ regurgitation) mitral regurgitation or aortic
regurgitation valvular disease
25. Received intravenous inotropes (e.g., dobutamine, dopamine, norepinephrine,
and vasopressin) within 30 days prior to the Screening Visit
26. Active malignancy with the exception of fully excised or treated basal cell
carcinoma, cervical carcinoma in-situ, or prostate cancer that is not currently
or expected, during the study, to be treated with radiation therapy,
chemotherapy, and/or surgical intervention, or hormonal treatment.
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR2021-000199-12-NL |
| ClinicalTrials.gov | NCT04811092 |
| CCMO | NL77852.028.21 |