A Study of Selexipag as Add-On Treatment to Standard of Care in Children With Pulmonary Arterial Hypertension (SALTO)

• ClinicalTrials.gov Identifier: NCT04175600
• Recruitment Status: Recruiting
• First Posted: November 25, 2019
• Last Update Posted: May 31, 2023
• Sponsor: Actelion
• Information provided by (Responsible Party): Actelion

Tracking Information

• First Submitted Date: November 8, 2019
• First Posted Date: November 25, 2019
• Last Update Posted Date: May 31, 2023
• Actual Study Start Date: January 16, 2020
• Estimated Primary Completion Date: December 9, 2024 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: November 21, 2019)

Time to Disease Progression [ Time Frame: 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.

• Original Primary Outcome Measures: Same as current

Current Secondary Outcome Measures (submitted: March 31, 2023)

• Percentage of Participants with Treatment-emergent Adverse Events (TEAEs) and Serious AEs [ Time Frame: Up to 5 years ]
  An adverse event (AE) is any untoward medical event that occurs in a participant administered an investigational product, and it does not necessarily indicate only events with clear causal relationship with the relevant investigational product. TEAEs are AEs with onset during the intervention period or that are a consequence of a pre-existing condition that has worsened since baseline. A SAE is an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life-threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly.
• Percentage of Participants with AEs Leading to Premature Discontinuation of Study Treatment [ Time Frame: Up to 5 years ]
  Percentage of participants with AEs leading to premature discontinuation of study treatment will be reported.
• Change from Baseline in Systolic and Diastolic Arterial Blood Pressure [ Time Frame: Baseline up to end of treatment (EOT) (up to 8 years) ]
  Change from baseline in systolic and diastolic arterial blood pressure to all assessed time points will be reported.
• Change from Baseline in Pulse Rate [ Time Frame: Baseline up to EOT (up to 8 years) ]
  Change from baseline in pulse rate to all assessed time points will be reported.
• Change from Baseline in Body Weight [ Time Frame: Baseline up to EOT (up to 8 years) ]
  Change from baseline in body weight to all assessed time points will be reported.
• Change from Baseline in Height [ Time Frame: Baseline up to EOT (up to 8 years) ]
  Change from baseline in height to all assessed time points will be reported.
• Sexual Maturation (Tanner Stage) Change from Baseline to all Assessed Time Points [ Time Frame: Up to 3 days after study treatment discontinuation (up to EOT) (multiple timepoints up to 8 years) ]
  The sexual maturation change as per Tanner stage will be assessed from baseline to all assessed time points. Tanner stage I is defined as no pubic hair at all (prepubertal Dominic state); stage II is defined as a small amount of long, downy hair with slight pigmentation at the base of the penis and scrotum (males) or on the labia majora (females); stage III is defined as when the hair becomes more coarse and curly, and begins to extend laterally; stage IV is defined as adult-like hair quality, extending across pubis but sparing medial thighs; and stage V is defined as when the: hair extends to medial surface of the thighs.
• Percentage of Participants with Treatment-emergent Electrocardiogram Abnormalities [ Time Frame: Baseline up to EOT (up to 8 years) ]
  Percentage of participants with treatment-emergent electrocardiogram abnormalities will be reported.
• Percentage of Participants with Treatment-emergent Marked Laboratory Abnormalities [ Time Frame: Baseline up to EOT (up to 8 years) ]
  Percentage of participants with treatment-emergent marked laboratory (serum chemistry [including pregnancy testing and thyroid markers] and hematology) abnormalities will be reported.
• Treatment-emergent Change from Baseline in Thyroid Stimulating Hormone [ Time Frame: Baseline up to EOT (up to 8 years) ]
  Treatment-emergent change from baseline in thyroid stimulating hormone over time will be reported.
• Time to First Clinical Event Committee (CEC)-confirmed Hospitalization or Death for PAH [ Time Frame: Until 7 days after study treatment discontinuation (Up to 8 years) ]
  Time to first CEC-confirmed hospitalization or death for PAH is the time (days) from randomization to first occurrence of CEC-confirmed hospitalization for PAH or death due to PAH up to 7 days after study intervention discontinuation.
• Trough Plasma Concentration at Steady-state (Ctrough,ss) of Selexipag and its Metabolite ACT-333679 [ Time Frame: Weeks 16, 24 and every 12 weeks thereafter (up to 8 years) ]
  Ctrough,ss is defined as the plasma concentration just prior to the morning dose, with the last study intervention administration one day prior to the pharmacokinetic sampling and will be reported for Selexipag and its metabolite ACT-333679.
• Change from Baseline at Week 24 in Log2 N-terminal Pro-brain Natriuretic Peptide (NT-proBNP) [ Time Frame: Baseline up to Week 24 ]
  The change from baseline at week 24 in log2 NT-proBNP will be reported.

Original Secondary Outcome Measures (submitted: November 21, 2019)

• Percentage of Participants with Treatment-emergent Adverse Events (TEAEs) and Serious AEs [ Time Frame: Up to 5 years ]
  An adverse event (AE) is any untoward medical event that occurs in a participant administered an investigational product, and it does not necessarily indicate only events with clear causal relationship with the relevant investigational product. TEAEs are AEs with onset during the intervention period or that are a consequence of a pre-existing condition that has worsened since baseline. A SAE is an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life-threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly.
• Percentage of Participants with AEs Leading to Premature Discontinuation of Study Treatment [ Time Frame: Up to 5 years ]
  Percentage of participants with AEs leading to premature discontinuation of study treatment will be reported.
• Treatment-emergent Change from Baseline in Systolic and Diastolic Arterial Blood Pressure [ Time Frame: Baseline up to end of treatment (EOT) (up to 8.3 years) ]
  Treatment-emergent change from baseline in systolic and diastolic arterial blood pressure to all assessed time points will be reported.
• Treatment-emergent Change from Baseline in Pulse Rate [ Time Frame: Baseline up to EOT (up to 8.3 years) ]
  Treatment-emergent change from baseline in pulse rate to all assessed time points will be reported.
• Treatment-emergent Change from Baseline in Body Weight [ Time Frame: Baseline up to EOT (up to 8.3 years) ]
  Treatment-emergent change from baseline in body weight to all assessed time points will be reported.
• Treatment-emergent Change from Baseline in Height [ Time Frame: Baseline up to EOT (up to 8.3 years) ]
  Treatment-emergent change from baseline in height to all assessed time points will be reported.
• Sexual Maturation (Tanner Stage) from Baseline to all Assessed Time Points [ Time Frame: Up to 3 days after study treatment discontinuation (up to EOT) (multiple timepoints up to 8.3 years) ]
  The sexual maturation as per Tanner stage will be assessed from baseline to all assessed time points. Tanner stage I is defined as no pubic hair at all (prepubertal Dominic state); stage II is defined as a small amount of long, downy hair with slight pigmentation at the base of the penis and scrotum (males) or on the labia majora (females); stage III is defined as when the hair becomes more coarse and curly, and begins to extend laterally; stage IV is defined as adult-like hair quality, extending across pubis but sparing medial thighs; and stage V is defined as when the: hair extends to medial surface of the thighs.
• Percentage of Participants with Treatment-emergent Electrocardiogram Abnormalities [ Time Frame: Baseline up to EOT (up to 8.3 years) ]
  Percentage of participants with treatment-emergent electrocardiogram abnormalities will be reported.
• Percentage of Participants with Treatment-emergent Marked Laboratory Abnormalities [ Time Frame: Baseline up to EOT (up to 8.3 years) ]
  Percentage of participants with treatment-emergent marked laboratory (serum chemistry [including pregnancy testing and thyroid markers] and hematology) abnormalities will be reported.
• Treatment-emergent Change from Baseline in Thyroid Stimulating Hormone [ Time Frame: Baseline up to EOT (up to 8.3 years) ]
  Treatment-emergent change from baseline in thyroid stimulating hormone over time will be reported.
• Time to First Clinical Event Committee (CEC)-confirmed Hospitalization and Death for PAH [ Time Frame: Until 7 days after study treatment discontinuation (Up to 8.3 years) ]
  Time to first CEC-confirmed hospitalization and death for PAH is the time (days) from randomization to first occurrence of CEC-confirmed hospitalization for PAH or death due to PAH up to 7 days after study intervention discontinuation.
• Trough Plasma Concentration at Steady-state (Ctrough,ss) of Selexipag and its Metabolite ACT-333679 [ Time Frame: Weeks 16, 24 and every 12 weeks thereafter (up to 8.3 years) ]
  Ctrough,ss is defined as the plasma concentration just prior to the morning dose, with the last study intervention administration one day prior to the pharmacokinetic sampling and will be reported for Selexipag and its metabolite ACT-333679.

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: A Study of Selexipag as Add-On Treatment to Standard of Care in Children With Pulmonary Arterial Hypertension
• Official Title: 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
• Brief Summary: 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.
• Detailed Description: 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.
• Study Type: Interventional
• Study Phase: Phase 3
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Double (Participant, Investigator); Primary Purpose: Treatment
• Condition: Hypertension, Pulmonary

Intervention

• Drug: Selexipag
  Selexipag tablet will be administered orally.
  Other Name: JNJ-67896049
• Drug: Placebo
  Matching placebo tablets will be administered orally.

Study Arms

• Experimental: 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.
  Intervention: Drug: Selexipag
• Placebo Comparator: Placebo
  Participants will receive matching placebo based on the body weight on Day 1 and will continue thereafter with twice daily dosing.
  Intervention: Drug: Placebo

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Recruiting
• Estimated Enrollment (submitted: March 31, 2023): 125
• Original Estimated Enrollment (submitted: November 21, 2019): 237
• Estimated Study Completion Date: January 10, 2028
• Estimated Primary Completion Date: December 9, 2024 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

• 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

Exclusion Criteria:

• 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

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 2 Years to 17 Years (Child)
• Accepts Healthy Volunteers: No

Contacts

Contact: Study Contact; 844-434-4210; Participate-In-This-Study@its.jnj.com

• Listed Location Countries: Canada, Australia, Belarus, Belgium, Brazil, Bulgaria, China, Colombia, Finland, France, Germany, Hungary, Ireland, Israel, Italy, Korea, Republic of, Lithuania, Malaysia, Mexico, Poland, Portugal, Russian Federation, Serbia, Spain, Sweden, Switzerland, Taiwan, Thailand, Turkey, Ukraine, United States, Vietnam
• Removed Location Countries: Argentina, Austria, Croatia, Denmark, Romania

Administrative Information

• NCT Number: NCT04175600
• Other Study ID Numbers: CR108716; 2019-002817-21 ( EudraCT Number ); AC-065A310 ( Other Identifier: Actelion )
• Has Data Monitoring Committee: Yes

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

IPD Sharing Statement

• Plan to Share IPD: Yes
• Plan Description: The data sharing policy of the Janssen Pharmaceutical Companies of Johnson & Johnson is available at www.janssen.com/clinical-trials/transparency. As noted on this site, requests for access to the study data can be submitted through Yale open Data Access (YODA) Project site at yoda.yale.edu
• URL: https://www.janssen.com/clinical-trials/transparency

• Current Responsible Party: Actelion
• Original Responsible Party: Janssen Research & Development, LLC
• Current Study Sponsor: Actelion
• Original Study Sponsor: Janssen Research & Development, LLC
• Collaborators: Not Provided

Investigators

• Study Director: Actelion Clinical Trial; Actelion

• PRS Account: Actelion
• Verification Date: May 2023