A Randomized, Multicenter, Double-Blind, Placebo-Controlled, Parallel-Group Study With Open-Label Extension Period to Assess the Efficacy and Safety of Selexipag as Add-On Treatment to Standard of Care in Children Aged >=2 to <18 Years With Pulmonary Arterial Hypertension
试验速览
- 阶段
- 3 期
- 状态
- 进行中（未招募）
- 发起方
- 入组人数
- 138
- 试验地点
- 204
- 主要终点
- Time to Disease Progression
研究概览
简要总结
The purpose of this study is to evaluate whether the addition of selexipag to standard of care treatment delays disease progression in children with Pulmonary Arterial Hypertension (PAH) in comparison to placebo.
详细描述
Pediatric PAH is a rare and progressive disorder associated with considerable morbidity and mortality. Given the significant medical need to develop treatments in children with PAH, further clinical studies in the pediatric population are therefore needed to provide more data for the management of PAH in children. Selexipag (JNJ-67896049) is an orally available, selective, and long-acting non-prostanoid agonist of the prostacyclin receptor approved and commercially available for the treatment of adult participants with PAH. Selexipag and its metabolite possess anti-fibrotic, anti-proliferative, and anti-thrombotic properties. Currently, no medicines targeting prostacyclin pathway are approved for pediatric use in PAH. An effective and orally available therapy acting on the prostacyclin receptor such as selexipag introduced at medically appropriate stage of PAH disease, and primarily in combination with current first-line oral PAH-specific medicines in participants in need of additional therapy because of insufficient disease control would represents a major advance to the therapeutic management of PAH pediatric participants. This study consists of a screening period of up to 6 weeks and a double-blind treatment period, including up-titration and maintenance periods, followed by a 3-year open-label extension period (OLEP) and a 30-day safety follow-up period that occurs after the last dose of study intervention (either double-blind or open-label). Safety, pharmacokinetic and efficacy assessments will be performed during the study. An Independent Data Monitoring Committee (IDMC) will be established to monitor data on an ongoing basis, to review interim data, and to ensure the continuing safety of the participants enrolled in this study. The approximate duration of the study is 8 years.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- Double (Participant, Investigator)
入排标准
- 年龄范围
- 2 Years 至 17 Years（Child）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Participants between greater than or equal to (>=) 2 and less than (<) 18 years of age weighing >=9 kilogram (kg) at randomization
- •Pulmonary arterial hypertension (PAH) diagnosis confirmed by documented historical right heart catheterization (RHC) performed at any time before participant's screening
- •PAH (World Health Organization [WHO] Group 1), including participants with Down syndrome, of the following etiologies: Idiopathic PAH (IPAH); Heritable PAH (HPAH); PAH associated with congenital heart disease (PAH-associated with congenital heart disease [aCHD]) (PAH with coincidental CHD [that is, a small atrial septal defect, ventricular septal defect, or patent ductus arteriosus that does not itself account for the development of elevated PVR] and if approved by the BCAC) and Post-operative PAH (persisting / recurring/ developing >=6 months after repair of CHD); Drug or toxin-induced; PAH associated with Human immunodeficiency virus (HIV)
- •WHO functional class (FC) II and III
- •Participants treated with at least 1 PAH-specific treatment, example, an Endothelin receptor antagonist (ERA) and/or a Phosphodiesterase type-5 (PDE-5) inhibitor/soluble guanylate cyclase stimulator, provided that the treatment dose(s) has been stable for at least 3 months prior to first dose of study intervention
排除标准
- •PAH due to portal hypertension, schistosomiasis, pulmonary veno-occlusive disease, and/or pulmonary capillary hemangiomatosis
- •PAH associated with Eisenmenger syndrome
- •Previous exposure to Uptravi (selexipag)
- •Known concomitant life-threatening disease with a life expectancy <12 months
- •Pregnant, planning to become pregnant, or lactating
- •Known allergies, hypersensitivity, or intolerance to selexipag or its excipients
研究组 & 干预措施
Selexipag
Participants will receive selexipag based on the body weight on Day 1 and will continue thereafter with twice daily dosing. Selexipag will be uptitrated during the first 12 weeks until the participants reaches the individual maximum tolerated dose (iMTD) or until a maximum dose corresponding to their baseline body-weight category is achieved. Uptitration is followed by a maintenance period after Week 12 until end of treatment (EOT), at the maximum tolerated dose. Participants will continue to receive pulmonary arterial hypertension (PAH)-specific concomitant therapies such as ERAs, PDE-5 inhibitors, and soluble guanylate cyclase stimulator as per local standard-of-care.
干预措施: Selexipag (Drug)
Placebo
Participants will receive matching placebo based on the body weight on Day 1 and will continue thereafter with twice daily dosing. Participants will continue to receive PAH-specific concomitant therapies such as ERAs, PDE-5 inhibitors, and soluble guanylate cyclase stimulator as per local standard-of-care.
干预措施: Placebo (Drug)
Selexipag
Participants will receive selexipag based on the body weight on Day 1 and will continue thereafter with twice daily dosing. Selexipag will be uptitrated during the first 12 weeks until the participants reaches the individual maximum tolerated dose (iMTD) or until a maximum dose corresponding to their baseline body-weight category is achieved. Uptitration is followed by a maintenance period after Week 12 until end of treatment (EOT), at the maximum tolerated dose. Participants will continue to receive pulmonary arterial hypertension (PAH)-specific concomitant therapies such as ERAs, PDE-5 inhibitors, and soluble guanylate cyclase stimulator as per local standard-of-care.
干预措施: SOC: Phosphodiesterase type 5 (PDE-5) inhibitor (Drug)
Selexipag
Participants will receive selexipag based on the body weight on Day 1 and will continue thereafter with twice daily dosing. Selexipag will be uptitrated during the first 12 weeks until the participants reaches the individual maximum tolerated dose (iMTD) or until a maximum dose corresponding to their baseline body-weight category is achieved. Uptitration is followed by a maintenance period after Week 12 until end of treatment (EOT), at the maximum tolerated dose. Participants will continue to receive pulmonary arterial hypertension (PAH)-specific concomitant therapies such as ERAs, PDE-5 inhibitors, and soluble guanylate cyclase stimulator as per local standard-of-care.
干预措施: SOC: Soluble guanylate cyclase stimulator (Drug)
Placebo
Participants will receive matching placebo based on the body weight on Day 1 and will continue thereafter with twice daily dosing. Participants will continue to receive PAH-specific concomitant therapies such as ERAs, PDE-5 inhibitors, and soluble guanylate cyclase stimulator as per local standard-of-care.
干预措施: Standard of Care (SOC): Endothelin receptor antagonist (Drug)
Open-Label Extension Period: Selexipag
Participants with a positive benefit/risk ratio of selexipag for PAH will be offered selexipag in the open label extension period. Participants on selexipag during the double-blind treatment period will continue treatment at their iMTD during the OLEP, for those previously on placebo, the iMTD will uptitrate selexipag during first 12 weeks until participant reaches iMTD. Participants will continue to receive PAH-specific concomitant therapies such as ERAs, PDE-5 inhibitors, and soluble guanylate cyclase stimulator as per local standard-of-care.
干预措施: SOC: Phosphodiesterase type 5 (PDE-5) inhibitor (Drug)
Open-Label Extension Period: Selexipag
Participants with a positive benefit/risk ratio of selexipag for PAH will be offered selexipag in the open label extension period. Participants on selexipag during the double-blind treatment period will continue treatment at their iMTD during the OLEP, for those previously on placebo, the iMTD will uptitrate selexipag during first 12 weeks until participant reaches iMTD. Participants will continue to receive PAH-specific concomitant therapies such as ERAs, PDE-5 inhibitors, and soluble guanylate cyclase stimulator as per local standard-of-care.
干预措施: SOC: Soluble guanylate cyclase stimulator (Drug)
Open-Label Extension Period: Selexipag
Participants with a positive benefit/risk ratio of selexipag for PAH will be offered selexipag in the open label extension period. Participants on selexipag during the double-blind treatment period will continue treatment at their iMTD during the OLEP, for those previously on placebo, the iMTD will uptitrate selexipag during first 12 weeks until participant reaches iMTD. Participants will continue to receive PAH-specific concomitant therapies such as ERAs, PDE-5 inhibitors, and soluble guanylate cyclase stimulator as per local standard-of-care.
干预措施: Selexipag (Drug)
Selexipag
Participants will receive selexipag based on the body weight on Day 1 and will continue thereafter with twice daily dosing. Selexipag will be uptitrated during the first 12 weeks until the participants reaches the individual maximum tolerated dose (iMTD) or until a maximum dose corresponding to their baseline body-weight category is achieved. Uptitration is followed by a maintenance period after Week 12 until end of treatment (EOT), at the maximum tolerated dose. Participants will continue to receive pulmonary arterial hypertension (PAH)-specific concomitant therapies such as ERAs, PDE-5 inhibitors, and soluble guanylate cyclase stimulator as per local standard-of-care.
干预措施: Standard of Care (SOC): Endothelin receptor antagonist (Drug)
Placebo
Participants will receive matching placebo based on the body weight on Day 1 and will continue thereafter with twice daily dosing. Participants will continue to receive PAH-specific concomitant therapies such as ERAs, PDE-5 inhibitors, and soluble guanylate cyclase stimulator as per local standard-of-care.
干预措施: SOC: Phosphodiesterase type 5 (PDE-5) inhibitor (Drug)
Placebo
Participants will receive matching placebo based on the body weight on Day 1 and will continue thereafter with twice daily dosing. Participants will continue to receive PAH-specific concomitant therapies such as ERAs, PDE-5 inhibitors, and soluble guanylate cyclase stimulator as per local standard-of-care.
干预措施: SOC: Soluble guanylate cyclase stimulator (Drug)
Open-Label Extension Period: Selexipag
Participants with a positive benefit/risk ratio of selexipag for PAH will be offered selexipag in the open label extension period. Participants on selexipag during the double-blind treatment period will continue treatment at their iMTD during the OLEP, for those previously on placebo, the iMTD will uptitrate selexipag during first 12 weeks until participant reaches iMTD. Participants will continue to receive PAH-specific concomitant therapies such as ERAs, PDE-5 inhibitors, and soluble guanylate cyclase stimulator as per local standard-of-care.
干预措施: Standard of Care (SOC): Endothelin receptor antagonist (Drug)
结局指标
主要结局
Time to Disease Progression
时间窗: From randomization up to 7 days after study treatment discontinuation (up to 5 years)
Time to disease progression is the time from randomization up to 7 days after study treatment discontinuation. Disease progression is defined as the first occurrence of either of the following components: Death (all causes), Atrial septostomy or Potts' anastomosis, or registration on lung transplant list, Hospitalization due to worsening pulmonary arterial hypertension (PAH), Clinical worsening of PAH.
Double-blind Period: Time to Disease Progression
时间窗: Placebo arm: Randomization (Day 1) up to 7 days after last dose in the DB treatment (maximum up to 199 weeks); Selexipag arm: Randomization (Day 1) up to 7 days after last dose in the DB treatment (maximum up to 213 weeks)
Time to disease progression: time from randomization to first Clinical Event Committee (CEC)-confirmed disease progression event occurring between date of randomization until double-blind end date (DBED) + 7 days. Disease progression event as adjudicated by CEC, defined as any of the following: death (all causes); atrial septostomy or Potts' anastomosis, or registration on lung transplant list; hospitalization due to worsening pulmonary arterial hypertension (PAH); clinical worsening of PAH. Clinical worsening of PAH was defined as initiation of new PAH-specific therapy or intravenous diuretics or continuous oxygen use and at least 1 of the following: worsening in World Health Organization (WHO) functional class (FC); new occurrence or worsening: of syncope, of at least 2 PAH symptoms (shortness of breath/dyspnea, chest pain, cyanosis, dizziness/near syncope, or fatigue), of signs of right heart failure not responding to oral diuretics. Kaplan-Meier method was used for estimation.
次要结局
- Change from Baseline in Systolic and Diastolic Arterial Blood Pressure(Baseline up to end of treatment (EOT) (up to 8 years))
- Change from Baseline in Pulse Rate(Baseline up to EOT (up to 8 years))
- Change from Baseline in Body Weight(Baseline up to EOT (up to 8 years))
- Change from Baseline in Height(Baseline up to EOT (up to 8 years))
- Sexual Maturation (Tanner Stage) Change from Baseline to all Assessed Time Points(Up to 3 days after study treatment discontinuation (up to EOT) (multiple timepoints up to 8 years))
- Percentage of Participants with Treatment-emergent Marked Laboratory Abnormalities(Baseline up to EOT (up to 8 years))
- Treatment-emergent Change from Baseline in Thyroid Stimulating Hormone(Baseline up to EOT (up to 8 years))
- Time to First Clinical Event Committee (CEC)-confirmed Hospitalization or Death for PAH(Until 7 days after study treatment discontinuation (Up to 8 years))
- Trough Plasma Concentration at Steady-state (Ctrough,ss) of Selexipag and its Metabolite ACT-333679(Weeks 16, 24 and every 12 weeks thereafter (up to 8 years))
- Change from Baseline at Week 24 in Log2 N-terminal Pro-brain Natriuretic Peptide (NT-proBNP)(Baseline up to Week 24)
- Percentage of Participants with Treatment-emergent Electrocardiogram Abnormalities(Baseline up to EOT (up to 8 years))
- Percentage of Participants with Treatment-emergent Adverse Events (TEAEs) and Serious AEs(Up to 5 years)
- Percentage of Participants with AEs Leading to Premature Discontinuation of Study Treatment(Up to 5 years)
- Double-blind Period: Change From Baseline in Growth Parameter: Height(Baseline (Day 1), Weeks 24, 48, 72, and 96)
- Double-blind Period: Change in log2 N-terminal Pro-brain Natriuretic Peptide (NT-proBNP) From Baseline to Week 24(Baseline (Day 1), Week 24)
- Double-blind Period: Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Treatment-emergent Serious AEs (TESAEs)(Placebo arm: Start of treatment (Day 1) up to 3 days after last dose in the DB treatment (maximum up to 198.42 weeks); Selexipag arm: Start of treatment (Day 1) up to 3 days after last dose in the DB treatment (maximum up to 212.42 weeks))
- Double-blind Period: Number of Participants With AEs Leading to Premature Discontinuation of Study Treatment(Placebo arm: Start of treatment (Day 1) up to last dose in the DB treatment (maximum up to 198 weeks); Selexipag arm: Start of treatment (Day 1) up to last dose in the DB treatment (maximum up to 212 weeks))
- Double-blind Period: Change From Baseline in Vital Signs: Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP)(Baseline (Day 1), Weeks 24, 48, 72, and 96)
- Double-blind Period: Change From Baseline in Vital Signs: Pulse Rate(Baseline (Day 1), Weeks 24, 48, 72, and 96)
- Double-blind Period: Change From Baseline in Growth Parameter: Body Weight(Baseline (Day 1), Weeks 24, 48, 72, and 96)
- Double-blind Period: Number of Participants With Shift From Baseline in Sexual Maturation (Tanner Stage)(Placebo arm: Baseline (Day 1) up to 3 days after last dose in the DB treatment (maximum up to 198.42 weeks); Selexipag arm: Baseline (Day 1) up to 3 days after last dose in the DB treatment (maximum up to 212.42 weeks))
- Double-blind Period: Number of Participants With Treatment-emergent Electrocardiogram (ECG) Abnormalities(Placebo arm: Start of treatment (Day 1) up to 3 days after last dose in the DB treatment (maximum up to 198.42 weeks); Selexipag arm: Start of treatment (Day 1) up to 3 days after last dose in the DB treatment (maximum up to 212.42 weeks))
- Double-blind Period: Number of Participants With Treatment-emergent (TE) Marked Laboratory Abnormalities(Placebo arm: Start of treatment (Day 1) up to 3 days after last dose in the DB treatment (maximum up to 198.42 weeks); Selexipag arm: Start of treatment (Day 1) up to 3 days after last dose in the DB treatment (maximum up to 212.42 weeks))
- Double-blind Period: Change From Baseline in Treatment-emergent Laboratory Parameter: Thyroid Stimulating Hormone(Baseline (Day 1), Weeks 24, 48, 72, and 96)
- Double-blind Period: Change From Baseline in Treatment-emergent Laboratory Parameter: Hemoglobin(Baseline (Day 1), Weeks 24, 48, 72, and 96)
- Double-blind Period: Change From Baseline in Treatment-emergent Laboratory Parameter: Platelets, Leukocytes(Baseline (Day 1), Weeks 24, 48, 72, and 96)
- Double-blind Period: Change From Baseline in Treatment-emergent Laboratory Parameter: Electrolytes (Sodium, Potassium, Calcium, Bicarbonate and Chloride)(Baseline (Day 1), Weeks 24, 48, 72, and 96)
- Double-blind Period: Change From Baseline in Treatment-emergent Laboratory Parameter: Transaminases (Alanine Aminotransferase [ALT] and Aspartate Aminotransferase [AST])(Baseline (Day 1), Weeks 24, 48, 72, and 96)
- Double-blind Period: Change From Baseline in Treatment-emergent Laboratory Parameter: Bilirubin(Baseline (Day 1), Weeks 24, 48, 72, and 96)
- Double-blind Period: Time to First Clinical Event Committee (CEC)-Confirmed Hospitalization or Death for Pulmonary Arterial Hypertension (PAH)(Placebo arm: Randomization (Day 1) up to 7 days after last dose in the DB treatment (maximum up to 199 weeks); Selexipag arm: Randomization (Day 1) up to 7 days after last dose in the DB treatment (maximum up to 213 weeks))
- Double-blind Period: Dose-normalized Steady-state Trough Concentrations (Ctrough,ss,dn) of Selexipag and Its Metabolite ACT-333679 by Age Cohort(Cohort (C) 1: Predose between Week (W) 16 to end of DB treatment period (maximum up to W212); C 2: Predose between Week 16 to end of DB treatment period (maximum up to W198); C 3: Predose between Week 16 to end of DB treatment period (maximum up to W96))
- Double-blind Period: Dose-normalized Steady-state Trough Concentrations (Ctrough,ss,dn) of Selexipag and Its Metabolite ACT-333679 by Body Weight (BW)(BW >=50kg: Predose between W16 to end of DB treatment period (maximum up to W212); BW >=25-<50kg: Predose between W16 to end of DB treatment period (maximum up to W198); BW >=9- <25kg: Predose between W16 to end of DB treatment period (maximum up to W175))