An Upcoming Clinical Study to Measure the Safety and Impact of a Drug Called Macitentan in Teenage and Adult Fontan Patients. (RUBATO OL)

Prospective, Multi-center, Single-arm, Open-label Long-term Study Assessing the Safety, Tolerability, and Effectiveness of Macitentan in Fontan-palliated Adult and Adolescent Subjects

The aim of this open-label (OL) trial is to study the long-term use of macitentan for up to 2 years in Fontan-palliated adult and adolescent patients beyond the 52 weeks of treatment in the parent RUBATO double-blind (DB) study (AC-055H301, NCT03153137). This OL trial studies the long-term effect of macitentan in Fontan-palliated patients as it is not known if the effect of macitentan is sustained beyond 52 weeks (end of the parent RUBATO DB study). In addition, the trial also studies the long-term safety of macitentan as this is also unknown. Furthermore, the opportunity will be given to patients who were on placebo in the parent RUBATO DB study to receive macitentan 10 mg and benefit from a potentially active treatment.

Study Overview

• Status: Terminated
• Conditions: Congenital Heart Disease With Fontan Circulation
• Intervention / Treatment: Drug: macitentan 10 mg

• Study Type: Interventional
• Enrollment (Actual): 112
• Phase: Phase 3

Contacts and Locations

Study Locations

• Australia
  • Adelaide, Australia, 5000
    • Royal Adelaide Hospital
  • Camperdown, Australia, 2050
    • Royal Prince Alfred Hospital
  • Chermside, Australia, 4032
    • The Prince Charles Hospital, Adult Congenital Heart Disease Unit
  • Parkville, Australia, 3052
    • Royal Children's Hospital
• Canada
  • Quebec, Canada, G1V 4G2
    • CHU de Quebec Universite Laval
• China
  • Beijing, China, 100029
    • Beijing Anzhen Hospital
  • Shanghai, China, 200127
    • Shanghai Children's Medical Center
• Czechia
  • Praha 5, Czechia, 150 06
    • Fakultni nemocnice v Motole
• Denmark
  • Copenhagen, Denmark, 2100
    • Rigshospitalet Kardiologisk Klinisk
• France
  • Paris, France, 75015
    • Hopital Necker - Enfants Malades
  • Pessac, France, 33604
    • Hôpital Cardiologique Du Haut-Lévêque
• New Zealand
  • Auckland, New Zealand, 1640
    • Auckland City Hospital
• Poland
  • Gdansk, Poland, 80-952
    • Uniwersyteckie Centrum Kliniczne
  • Krakow, Poland, 31-202
    • Krakowski Szpital Specjalityczny im. Jana Pawla II, Oddzial Kliniczny Chorob Serca i Naczyn
  • Wrocław, Poland, 51-124
    • Wojewodzki Szpital Specjalistyczny We Wroclawiu
• Taiwan
  • Taipei, Taiwan, 10002
    • National Taiwan University Hospital
• United Kingdom
  • Birmingham, United Kingdom, B15 2TH
    • Queen Elizabeth Hospital
• United States
  • Massachusetts
    • Boston, Massachusetts, United States, 02114
      • Massachusetts General Hospital Heart Center
  • Washington
    • Spokane, Washington, United States, 99202
      • Providence Medical Research Providence Health Care

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 12 years and older (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Written informed consent/assent from the subject and/or a legal representative prior to initiation of any study-mandated procedures.
• Subjects who have completed Week 52 of the parent AC-055H301/RUBATO DB study (NCT03153137)

• Women of childbearing potential must:

  1. have a negative serum pregnancy test prior to first intake of OL study drug, and,
  2. agree to perform monthly pregnancy tests up to the end of the safety follow up (S-FU) period, and,
  3. use reliable methods of contraception from enrollment up to at least 30 days after study treatment discontinuation.

Exclusion Criteria:

• Clinical worsening leading to medical interventions including reoperation of Fontan circulation (Fontan take-down) during the enrollment period
• Systolic blood pressure < 90 mmHg (< 85 mmHg for subjects < 18 years old and < 150 cm of height) at rest
• Criteria related to macitentan use
• Any known factor or disease that may interfere with treatment compliance or full participation in the study

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Open-label treatment period; oral administration of 10 mg macitentan once daily	Drug: macitentan 10 mg; macitentan 10 mg, film-coated tablet, oral use

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Participants With Treatment-emergent Adverse Events (TEAEs)	An adverse event 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. Any AE occurring at or after the study treatment start up to 30 days after end of treatment (EOT) (limits included) within the analysis set was considered to be treatment-emergent.	Up to 133 weeks
Number of Participants With Treatment-emergent Serious AEs (TESAEs)	An adverse event 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. SAE is any AE that results in: death, persistent or significant disability/incapacity, requires inpatient hospitalization or prolongation of existing hospitalization, is life-threatening experience, is a congenital anomaly/birth defect and may jeopardize participant and/or may require medical or surgical intervention to prevent one of the outcomes listed above. Any SAE occurring at or after the study treatment start up to 30 days after EOT (limits included) within the analysis set was considered to be TESAEs.	Up to 133 weeks
Number of Participants With TEAEs Leading to Death	An adverse event 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. Any AE occurring at or after the study treatment start up to 30 days after EOT (limits included) within the analysis set was considered to be treatment-emergent.	Up to 133 weeks
Number of Participants With TEAEs Leading to Premature Discontinuation of Study Treatment	An adverse event 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. Any AE occurring at or after the study treatment start up to 30 days after EOT (limits included) within the analysis set was considered to be treatment-emergent.	Up to 133 weeks
Number of Participants With Treatment-emergent Marked Laboratory Abnormalities up to 30 Days After Study Treatment Discontinuation	Number of participants with treatment-emergent marked laboratory abnormalities (Hemoglobin [gram/Liter {g/L}], Platelets [giga/L {10^9 cells/L}], Leukocytes [10^9 cells/L], Lymphocytes [10^9 cells/L], Neutrophils [10^9 cells/L], Prothrombin International Normalized Ratio [PINR;Ratio], Aspartate Aminotransferase [Units/L {U/L}], Bilirubin [micromoles/L {mcmol/L}], Alkaline Phosphatase [U/L], Glomerular Filtration Rate [milliliter/minute/1.73 meter square], Glucose [millimoles/L {mmol/L}], Potassium [mmol/L], Sodium [mmol/L], Triglycerides [mmol/L] were reported. Abnormalities that occurred after study treatment start and up to 30 days after study treatment discontinuation, that were not present at baseline, were treatment-emergent. Marked laboratory abnormalities reported for at least 1 participant were reported in this outcome measure. >=:greater than or equal to; >:greater than; <:less than; ULN: upper limit of normal; L:Low, H:High, LLL:lower/worse than LL, HHH:higher/worse than HH.	Up to 133 weeks
Change From Baseline in Hemoglobin Over Time	Change from baseline in hemoglobin over time was reported in this outcome measure.	Baseline up to Week 130
Change From Baseline in Hematocrit Over Time	Change from baseline in hematocrit over time was reported in this outcome measure.	Baseline up to Week 130
Change From Baseline in Leukocytes, Neutrophils, Lymphocytes, and Platelets Over Time	Change from baseline in leukocytes, neutrophils, lymphocytes, and platelets over time were reported in this outcome measure.	Baseline up to Week 130
Change From Baseline in Systolic and Diastolic Arterial Blood Pressure (BP) Over Time	Change from baseline in systolic and diastolic arterial BP over time was reported in this outcome measure.	Baseline up to Week 130
Change From Baseline in Pulse Rate Over Time	Change from baseline in pulse rate over time was reported in this outcome measure.	Baseline up to Week 130
Change From Baseline in Peripheral Oxygen Saturation (SpO2) Over Time	Change from baseline in SpO2 over time was reported in this outcome measure.	Baseline up to Week 130
Change From Baseline in Body Weight Over Time	Change from baseline in body weight over time was reported in this outcome measure.	Baseline up to Week 130
Change From Baseline in Alanine Aminotransferase (ALT), Aspartate Aminotransferase (AST), Alkaline Phosphatase (AP), and Gamma Glutamyl Transferase (GGT) Over Time	Change from baseline in ALT, AST, AP, and GGT over time were reported in this outcome measure.	Baseline up to Week 130
Change From Baseline in Bilirubin, Direct Bilirubin, and Creatinine Over Time	Change from baseline in bilirubin, direct bilirubin, and creatinine over time were reported in this outcome measure.	Baseline up to Week 130
Change From Baseline in Glomerular Filtration Rate (GFR) Over Time	Change from baseline in GFR over time was reported in this outcome measure.	Baseline up to Week 130
Change From Baseline in Prothrombin Time Over Time	Change from baseline in prothrombin time over time was reported in this outcome measure.	Baseline up to Week 130
Change From Baseline in Prothrombin International Normalized Ratio Over Time	Change from baseline in prothrombin international normalized ratio over time was reported in this outcome measure.	Baseline up to Week 130

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change From Baseline in Peak Oxygen Uptake/Consumption (VO2)	Change from baseline in peak VO2 was reported in this outcome measure.	Baseline, Week 52, and Week 104
Change From Baseline in Mean Count Per Minute of Daily Physical Activity Measured by Accelerometer (PA-Ac)	Change from baseline in mean count per minute of daily PA-Ac was reported in this outcome measure.	Baseline, Week 26, Week 52, Week 78, and Week 104

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change from baseline in peak oxygen uptake (VO2)	Peak VO2 is measured from baseline to each scheduled time point to assess the effect of macitentan on exercise capacity.	From Enrollment to End-of-Treatment visit (Week 104)
Change from baseline in mean count per minute of daily physical activity measured by accelerometer (PA-Ac)	The daily physical activity (counts/min) of the subject is assessed via accelerometer during daytime. The mean count per minute of daily PA-Ac will be measured from baseline to each scheduled time point.	From Enrollment to End-of-Treatment visit (Week 104)

Collaborators and Investigators

• Sponsor: Actelion
• Collaborators: Henry Ford Health System; Covance; Medidata Solutions; Almac Clinical Technologies; ActiGraph LLC
• Investigators: Study Director: Thierry Francis Briand, MD, Actelion

Study record dates

Study Major Dates

• Study Start (Actual): April 11, 2019
• Primary Completion (Actual): January 18, 2022
• Study Completion (Actual): January 18, 2022

Study Registration Dates

• First Submitted: November 21, 2018
• First Submitted That Met QC Criteria: December 11, 2018
• First Posted (Actual): December 14, 2018

Study Record Updates

• Last Update Posted (Estimate): March 7, 2023
• Last Update Submitted That Met QC Criteria: March 6, 2023
• Last Verified: March 1, 2023

More Information

Terms related to this study

• Keywords: macitentan; Congenital Heart Failure; Univentricular Heart; Cavopulmonary Anastomosis; Fontan circulation
• Additional Relevant MeSH Terms: Cardiovascular Diseases; Congenital Abnormalities; Cardiovascular Abnormalities; Heart Diseases; Heart Defects, Congenital; Molecular Mechanisms of Pharmacological Action; Endothelin Receptor Antagonists; Endothelin A Receptor Antagonists; Endothelin B Receptor Antagonists; Macitentan
• Other Study ID Numbers: AC-055H302; 2018-002821-45 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD 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 Access (YODA) Project site at yoda.yale.edu

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No