Resumen

Los objetivos de este estudio son evaluar la eficacia y seguridad del tratamiento con sotatercept (MK-7962) (más tratamiento de base para hipertensión arterial pulmonar [HAP]) versus placebo (más tratamiento de base para HAP) a las 24 semanas en adultos con HAP. La hipótesis principal del estudio es que los participantes que reciban sotatercept presentarán una mejora en la distancia recorrida en la prueba de marcha de 6 minutos (DM6M) a las 24 semanas en comparación con los participantes que reciban placebo.

Descripción detallada

Este es un estudio fase 3, aleatorizado, doble ciego, controlado con placebo, multicéntrico, de grupos paralelos en sujetos con HAP sintomática que presentan HAP idiopática o hereditaria, HAP asociada a enfermedades del tejido conectivo (ETC), HAP inducida por fármacos o toxinas, HAP posterior a corrección de cortocircuito, o HAP que se presenta al menos 1 año después de la corrección de cardiopatías congénitas (CC), y que actualmente reciben tratamiento de base para HAP. El criterio de valoración primario de eficacia del estudio es la capacidad de ejercicio, medida por la distancia recorrida en la prueba de marcha de 6 minutos (DM6M) evaluada a las 24 semanas desde el inicio del tratamiento. La duración del estudio será de aproximadamente 2 años. Se utilizará una prueba de Wilcoxon estratificada para el análisis del criterio de valoración primario, con la imputación apropiada de datos faltantes, según se detalla en el Plan de Análisis Estadístico. Un Comité Independiente de Monitoreo de Datos (CIMD), externo y no ciego, supervisará la seguridad de los participantes durante todo el estudio. Los participantes que completen este estudio serán elegibles para recibir sotatercept en un estudio de extensión abierto separado.

Elegibilidad

Edad mínima: 18 YearsSexo: ALL

Criterios de inclusión

Age ≥ 18 years
Documented diagnostic right heart catheterization (RHC) at any time prior to screening confirming the diagnosis of World Health Organization (WHO) pulmonary arterial hypertension (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 Functional Class (FC) II or III
Baseline RHC performed during the Screening Period documenting a minimum pulmonary vascular resistance (PVR) of ≥ 5 Wood units (WU) and a pulmonary capillary wedge pressure (PCWP) or left ventricular end-diastolic pressure of ≤ 15 mmHg.
On stable doses of background PAH therapy and diuretics (i.e., patient-specific dose goal for each therapy already achieved) for at least 90 days prior to screening; for infusion prostacyclins, dose adjustment within 10% of optimal dose is allowed per medical practice
Background PAH therapy refers to approved PAH-specific medications and may consist of monotherapy or combination therapy with ERA, PDE5 inhibitors, soluble guanylate cyclase stimulators, and/or prostacyclin analogues or receptor agonists. Background PAH therapy should be stable at least 90 days prior to screening and remain stable throughout the study
Stable diuretic therapy is defined as no addition of a new diuretic and no switching of a pre-existent oral diuretic to parenteral administration; however, dose adjustments (up or down) in pre-existent oral diuretics are acceptable
Minute Walk Distance (6MWD) ≥ 150 and ≤ 500 m repeated twice at screening (measured at least 4 hours apart, but no longer than 1 week), and both values are within 15% of each other (calculated from the highest value)
Females of childbearing potential must:
Have 2 negative urine or serum pregnancy tests as verified by the investigator prior to starting study therapy; she must agree to ongoing urine or serum pregnancy testing during 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:
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

Criterios de exclusión

Diagnosis of pulmonary hypertension 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. Exclusions in PAH Group I should also include schistosomiasis associate PAH and pulmonary veno occlusive disease
Hemoglobin (Hgb) at screening above gender-specific upper limit of normal (ULN), per local laboratory test
Baseline platelet count \< 50,000/mm\^3 (\< 50.0 x 109/L) at screening
Uncontrolled systemic hypertension as evidenced by sitting systolic blood pressure \> 160 mmHg or sitting diastolic blood pressure \> 100 mmHg during screening visit after a period of rest
Baseline systolic blood pressure \< 90 mmHg at screening
Pregnant or breastfeeding women
Any of the following clinical laboratory values at the screening visit:
Estimated glomerular filtration rate (eGFR) \< 30 mL/min/m2 (as defined by the Modification of Diet in Renal Disease \[MDRD\] equation)
Serum alanine aminotransferase, aspartate aminotransferase, or total bilirubin levels \> 3 × ULN (bilirubin criterion waived if there is a documented history of Gilbert's syndrome)
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
Prior exposure to sotatercept (ACE-011) or luspatercept (ACE 536) and/or excipients or known allergic reaction to either one
History of full pneumonectomy
Pulmonary function test (PFT) values of forced vital capacity (FVC) \< 60% predicted at the screening visit or within 6 months prior to the screening visit. If PFT is not available, a chest CT scan showing more than mild interstitial lung disease (ILD) at the screening visit or 1 year prior to it
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)
History of more than mild obstructive sleep apnea that is untreated
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)
History of restrictive, constrictive or congestive cardiomyopathy
History of atrial septostomy within 180 days prior to the screening visit
Electrocardiogram (ECG) with Fridericia's corrected QT interval (QTcF) \> 500 ms during the screening period
Personal or family history of long QT syndrome (LQTS) or sudden cardiac death
Left ventricular ejection fraction \< 45% on historical echocardiogram within 6 months prior to the screening visit
Any symptomatic coronary disease events (prior myocardial infarction, percutaneous coronary intervention, coronary artery bypass graft surgery, or cardiac anginal chest pain) within 6 months prior to the screening visit. Note: Anginal pain can be ignored as an exclusion criterion if coronary angiography shows no obstructions
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, vasopressin) within 30 days prior to the screening visit

Intervenciones

biological

Sotatercept

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

drug

Placebo

Placebo administered subcutaneously (SC) every 21 days plus background PAH therapy.

drug

Background PAH Therapy

Background PAH therapy may consist 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.

Ubicaciones

Hospital Universitario Austral ( Site 1901)

Pilar, Buenos Aires, Argentina

Instituto de Investigaciones Clinicas Quilmes ( Site 1903)

Quilmes, Buenos Aires, Argentina

Centro Medico Dra De Salvo ( Site 1904)

Buenos Aires, Buenos Aires F.D., Argentina

Sanatorio Parque ( Site 1905)

Rosario, Santa Fe Province, Argentina

Hospital Provincial Dr. Jose M. Cullen ( Site 1902)

Santa Fe, Argentina

Estudio fase 3, aleatorizado, doble ciego, controlado con placebo, para comparar la eficacia y seguridad de sotatercept versus placebo añadido al tratamiento de base para hipertensión arterial pulmonar (HAP) en el tratamiento de la HAP