Clinical Study Assessing the Efficacy and Safety of Macitentan in Fontan-palliated Subjects (RUBATO)

Prospective, Multi-center, Double-blind, Randomized, Placebo-controlled, Parallel-group Study Assessing the Efficacy and Safety of Macitentan in Fontan-palliated Adult and Adolescent Subjects

The primary objective is to assess the effect of macitentan 10 mg as compared to placebo on exercise capacity through cardiopulmonary exercise testing.

Study Overview

• Status: Completed
• Conditions: Congenital Heart Disease
• Intervention / Treatment: Drug: Macitentan 10 mg; Drug: Placebo

• Study Type: Interventional
• Enrollment (Actual): 142
• 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
  • South Brisbane, Australia, 4101
    • Queensland Children's Hospital
  • Westmead, Australia, 2145
    • Westmead Hospital
• Canada
  • Quebec, Canada, G1V 4G2
    • CHU de Quebec Universite Laval
• China
  • Beijing, China, 100029
    • Beijing Anzhen Hospital
  • Beijing, China, 100037
    • Beijing Fuwai Hospital
  • Shanghai, China, 200127
    • Shanghai Children's Medical Center
  • Wuhan, China, 430022
    • Wuhan Asia Heart Hospital
• Czechia
  • Praha 5, Czechia, 150 06
    • Fakultni nemocnice v Motole
• Denmark
  • Copenhagen, Denmark, 2100
    • Rigshospitalet Kardiologisk Klinisk
• France
  • Montpellier Cedex 5, France, 34295
    • CHU Arnaud de Villeneuve
  • Paris, France, 75015
    • Hôpital Necker - Enfants Malades
  • Pessac, France, 33604
    • Hôpital Cardiologique Du Haut-Lévêque
• Germany
  • Berlin, Germany, 13353
    • Deutsches Herzzentrum Berlinklinik Für Angeborene Herzfehler
  • München, Germany, 80636
    • Deutsches Herzzentrum München
• 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
  • Kraków, Poland, 30-663
    • Uniwersytecki Szpital Dzieciecy w Krakowie
  • Wrocław, Poland, 51-124
    • Wojewódzki Szpital Specjalistyczny we Wrocławiu
• Taiwan
  • Taipei, Taiwan, 100
    • National Taiwan University Hospital
• United Kingdom
  • Birmingham, United Kingdom, B15 2TH
    • Queen Elizabeth Hospital
  • Birmingham, United Kingdom, B4 6NH
    • Birmingham Children's Hospital
• United States
  • Alabama
    • Birmingham, Alabama, United States, 35233-1935
      • University of Alabama at Birmingham
  • California
    • Los Angeles, California, United States, 90095
      • UCLA
  • Massachusetts
    • Boston, Massachusetts, United States, 02114
      • Massachusetts General Hospital Heart Center
  • Ohio
    • Columbus, Ohio, United States, 43205
      • Nationwide Children's Hospital
  • Texas
    • Houston, Texas, United States, 77030-2303
      • Texas Children's Hospital
  • Washington
    • Spokane, Washington, United States, 99202
      • Providence Medical Research Providence Health Care

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 12 years and older (ADULT, OLDER_ADULT, CHILD)
• 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
• Fontan-palliated subjects with either intra-atrial lateral tunnel total cavopulmonary connection (LT-TCPC), or extra cardiac tunnel TCPC (EC-TCPC) surgery > 1 year before Screening. Either LT- or EC-TCPC can be primary or secondary to atrio-pulmonary connection
• New York Heart Association (NYHA) functional class (FC) II or III (assessed by the investigator using the Specific Activity Scale
• Women of childbearing potential must have a negative serum pregnancy test use reliable contraception

Exclusion Criteria:

• Pattern of Fontan circulation severity
• Deterioration of the Fontan-palliated condition.
• Limitations to Cardiopulmonary exercise testing (CPET)
• Peak VO2 < 15 mL/kg/min.
• 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: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: QUADRUPLE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: Macitentan; Macitentan 10 mg per day; film-coated tablet; oral use	Drug: Macitentan 10 mg; film-coated tablet; oral use
PLACEBO_COMPARATOR: Placebo; film-coated tablet; oral use	Drug: Placebo; film-coated tablet; oral use

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change From Baseline in Peak Oxygen Uptake/Consumption (VO2) Up to Week 16	Change from baseline in peak VO2 up to Week 16 was reported.	Baseline up to Week 16

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change From Baseline in Peak VO2 Up to Week 52	Change from baseline in peak VO2 up to Week 52 was reported.	Baseline up to Week 52
Change From Baseline in Mean Count Per Minute of Daily Physical Activity Measured by Accelerometer (PA-Ac) Up to Week 16	Change from baseline in mean count per minute of daily PA-Ac up to Week 16 was reported. The daily physical activity (counts per min) of the participant was assessed via accelerometer during daytime. The accelerometer was given to the participant at Visit 1, and data was collected for 9 consecutive daily daytime periods after Visit 1 (baseline) to Visit 4 (Week 16).	Baseline up to Week 16
Number of Participants With Treatment-emergent Serious Adverse Events (SAEs)	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.	Up to 56 weeks
Number of Participants With Treatment-emergent Adverse Events (AEs)	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.	Up to 56 weeks
Number of Participants With AEs Leading to Premature Discontinuation of Study Treatment	Number of participants with AEs leading to premature discontinuation of study treatment was reported. AEs leading to premature discontinuation of study treatment were those with action taken with study drug reported as 'permanently discontinued' by the investigator.	Up to 56 weeks
Change From Baseline in Systolic and Diastolic Arterial Blood Pressure (BP)	Change from baseline in systolic and diastolic arterial BP at Week 8, Week 16, Week 32 and Week 52 was reported.	Baseline, Week 8, Week 16, Week 32 and Week 52
Change From Baseline in Pulse Rate	Change from baseline in pulse rate at Week 8, Week 16, Week 32 and Week 52 was reported.	Baseline, Week 8, Week 16, Week 32 and Week 52
Change From Baseline in Oxygen Saturation (SpO2)	Change from baseline in SpO2 was reported.	Baseline, Week 8, Week 16, Week 32 and Week 52
Change From Baseline in Body Weight	Change from baseline in body weight was reported.	Baseline, Week 8, Week 16, Week 32 and Week 52
Number of Participants With Treatment-emergent Markedly Abnormal Laboratory Values	Number of participants with treatment-emergent markedly laboratory abnormal laboratory values were reported. Abnormal values for platelets (LL < 75); Lymphocytes (HH > 4.0); Neutrophils (LL < 1.5); Prothrombin International Normalized Ratio: HH (greater than and equal to [>=] 1.5 upper limit of normal [ULN]), Ratio: HH >= 2.5 ULN); Bilirubin (HH >= 2 ULN); Alkaline Phosphatase (HH > 2.5 ULN); Glomerular Filtration Rate (LL < 60); Glucose (HH > 8.9); Triglycerides (HH > 3.42). Here "HH" refers to values above the normal range, where H stands for "high" and "LL" refers to values below the normal range where L stands for "low".	Up to 56 weeks
Change From Baseline in Hemoglobin	Change from baseline in hemoglobin was reported.	Baseline, Week 8, Week 16, Week 32 and Week 52
Change From Baseline in Hematocrit	Change from baseline in hematocrit was reported.	Baseline, Week 8, Week 16, Week 32 and Week 52
Change From Baseline in Erythrocytes and Reticulocytes	Change from baseline in erythrocytes and reticulocytes at Week 8, Week 16, Week 32 and Week 52 was reported.	Baseline, Week 8, Week 16, Week 32 and Week 52
Change From Baseline in Leucocytes, Neutrophils, Lymphocytes, Monocytes, Eosinophils, Basophils and Platelets	Change from baseline in leucocytes, neutrophils, lymphocytes, monocytes, eosinophils, basophils and platelets at Week 8, Week 16, Week 32 and Week 52 was reported.	Baseline, Week 8, Week 16, Week 32 and Week 52
Change From Baseline in Prothrombin Time	Change from baseline in prothrombin time was reported.	Baseline, Week 8, Week 16, Week 32 and Week 52
Change From Baseline in Prothrombin International Normalized Ratio	Change from baseline in prothrombin international normalized ratio was reported.	Baseline, Week 8, Week 16, Week 32 and Week 52
Change From Baseline in Alanine Aminotransferase (ALT), Aspartate Aminotransferase (AST) and Alkaline Phosphatase (AP)	Change from baseline in ALT, AST and AP were reported.	Baseline, Week 8, Week 16, Week 32 and Week 52
Change From Baseline in Bilirubin and Direct Bilirubin	Change from baseline in bilirubin and direct bilirubin was reported.	Baseline, Week 8, Week 16, Week 32 and Week 52
Change From Baseline in Gamma Glutamyl Transferase	Change from baseline in gamma glutamyl transferase was reported.	Baseline, Week 8, Week 16, Week 32 and Week 52
Change From Baseline in Creatinine	Change from baseline in creatinine was reported.	Baseline, Week 8, Week 16, Week 32 and Week 52
Change From Baseline in Urea Nitrogen	Change from baseline in urea nitrogen was reported.	Baseline, Week 8, Week 16, Week 32 and Week 52
Change From Baseline in Urate	Change from baseline in urate was reported.	Baseline, Week 8, Week 16, Week 32 and Week 52
Change From Baseline in Glucose, Cholesterol, Triglycerides, Sodium, Potassium, Chloride and Calcium	Change from baseline in glucose, cholesterol, triglycerides, sodium, potassium, chloride and calcium was reported.	Baseline, Week 8, Week 16, Week 32 and Week 52
Change From Baseline in Albumin and Protein	Change from baseline in albumin and protein was reported.	Baseline, Week 8, Week 16, Week 32 and Week 52
Change From Baseline in Alpha Fetoprotein	Change from baseline in alpha fetoprotein was reported.	Baseline, Week 8, Week 16, Week 32 and Week 52
Change From Baseline in Cystatin C	Change from baseline in cystatin C was reported.	Baseline, Week 8, Week 16, Week 32 and Week 52

Collaborators and Investigators

• Sponsor: Actelion

Study record dates

Study Major Dates

• Study Start (ACTUAL): August 14, 2017
• Primary Completion (ACTUAL): June 30, 2021
• Study Completion (ACTUAL): July 26, 2021

Study Registration Dates

• First Submitted: May 12, 2017
• First Submitted That Met QC Criteria: May 12, 2017
• First Posted (ACTUAL): May 15, 2017

Study Record Updates

• Last Update Posted (ACTUAL): September 13, 2022
• Last Update Submitted That Met QC Criteria: August 18, 2022
• Last Verified: August 1, 2022

More Information

Terms related to this study

• 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-055H301; 2016-003320-23 (EUDRACT_NUMBER)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

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