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

Primary Purpose

Congenital Heart Disease

Status
Completed
Phase
Phase 3
Locations
International
Study Type
Interventional
Intervention
Macitentan 10 mg
Placebo
Sponsored by
Actelion
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Congenital Heart Disease

Eligibility Criteria

12 Years - undefined (Child, Adult, Older Adult)All SexesDoes not accept healthy volunteers

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

Sites / Locations

  • University of Alabama at Birmingham
  • UCLA
  • Massachusetts General Hospital Heart Center
  • Nationwide Children's Hospital
  • Texas Children's Hospital
  • Providence Medical Research Providence Health Care
  • Royal Adelaide Hospital
  • Royal Prince Alfred Hospital
  • The Prince Charles Hospital, Adult Congenital Heart Disease Unit
  • Royal Children's Hospital
  • Queensland CHILDREN'S HOSPITAL
  • Westmead Hospital
  • CHU de Québec Université Laval
  • Beijing Anzhen Hospital
  • Beijing Fuwai Hospital
  • Shanghai Children's Medical Center
  • Wuhan Asia Heart Hospital
  • Fakultni nemocnice v Motole
  • Rigshospitalet Kardiologisk Klinisk
  • CHU Arnaud de Villeneuve
  • Hôpital Necker - Enfants Malades
  • Hôpital Cardiologique Du Haut-Lévêque
  • Deutsches Herzzentrum Berlinklinik Für Angeborene Herzfehler
  • Deutsches Herzzentrum München
  • Auckland City Hospital
  • Uniwersyteckie Centrum Kliniczne
  • Krakowski Szpital Specjalityczny im. Jana Pawla II, Oddzial Kliniczny Chorob Serca i Naczyn
  • Uniwersytecki Szpital Dzieciecy w Krakowie
  • Wojewódzki Szpital Specjalistyczny We Wrocławiu
  • National Taiwan University Hospital
  • Queen Elizabeth Hospital
  • Birmingham Children's Hospital

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Placebo Comparator

Arm Label

Macitentan

Placebo

Arm Description

Macitentan 10 mg per day; film-coated tablet; oral use

film-coated tablet; oral use

Outcomes

Primary Outcome Measures

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.

Secondary Outcome Measures

Change From Baseline in Peak VO2 Up to Week 52
Change from baseline in peak VO2 up to Week 52 was reported.
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).
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.
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.
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.
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.
Change From Baseline in Pulse Rate
Change from baseline in pulse rate at Week 8, Week 16, Week 32 and Week 52 was reported.
Change From Baseline in Oxygen Saturation (SpO2)
Change from baseline in SpO2 was reported.
Change From Baseline in Body Weight
Change from baseline in body weight was reported.
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".
Change From Baseline in Hemoglobin
Change from baseline in hemoglobin was reported.
Change From Baseline in Hematocrit
Change from baseline in hematocrit was reported.
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.
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.
Change From Baseline in Prothrombin Time
Change from baseline in prothrombin time was reported.
Change From Baseline in Prothrombin International Normalized Ratio
Change from baseline in prothrombin international normalized ratio was reported.
Change From Baseline in Alanine Aminotransferase (ALT), Aspartate Aminotransferase (AST) and Alkaline Phosphatase (AP)
Change from baseline in ALT, AST and AP were reported.
Change From Baseline in Bilirubin and Direct Bilirubin
Change from baseline in bilirubin and direct bilirubin was reported.
Change From Baseline in Gamma Glutamyl Transferase
Change from baseline in gamma glutamyl transferase was reported.
Change From Baseline in Creatinine
Change from baseline in creatinine was reported.
Change From Baseline in Urea Nitrogen
Change from baseline in urea nitrogen was reported.
Change From Baseline in Urate
Change from baseline in urate was reported.
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.
Change From Baseline in Albumin and Protein
Change from baseline in albumin and protein was reported.
Change From Baseline in Alpha Fetoprotein
Change from baseline in alpha fetoprotein was reported.
Change From Baseline in Cystatin C
Change from baseline in cystatin C was reported.

Full Information

First Posted
May 12, 2017
Last Updated
August 18, 2022
Sponsor
Actelion
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1. Study Identification

Unique Protocol Identification Number
NCT03153137
Brief Title
Clinical Study Assessing the Efficacy and Safety of Macitentan in Fontan-palliated Subjects
Acronym
RUBATO
Official Title
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
Study Type
Interventional

2. Study Status

Record Verification Date
August 2022
Overall Recruitment Status
Completed
Study Start Date
August 14, 2017 (Actual)
Primary Completion Date
June 30, 2021 (Actual)
Study Completion Date
July 26, 2021 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Actelion

4. Oversight

Studies a U.S. FDA-regulated Drug Product
Yes
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
Yes

5. Study Description

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

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Congenital Heart Disease

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 3
Interventional Study Model
Parallel Assignment
Masking
ParticipantCare ProviderInvestigatorOutcomes Assessor
Allocation
Randomized
Enrollment
142 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Macitentan
Arm Type
Experimental
Arm Description
Macitentan 10 mg per day; film-coated tablet; oral use
Arm Title
Placebo
Arm Type
Placebo Comparator
Arm Description
film-coated tablet; oral use
Intervention Type
Drug
Intervention Name(s)
Macitentan 10 mg
Intervention Description
film-coated tablet; oral use
Intervention Type
Drug
Intervention Name(s)
Placebo
Intervention Description
film-coated tablet; oral use
Primary Outcome Measure Information:
Title
Change From Baseline in Peak Oxygen Uptake/Consumption (VO2) Up to Week 16
Description
Change from baseline in peak VO2 up to Week 16 was reported.
Time Frame
Baseline up to Week 16
Secondary Outcome Measure Information:
Title
Change From Baseline in Peak VO2 Up to Week 52
Description
Change from baseline in peak VO2 up to Week 52 was reported.
Time Frame
Baseline up to Week 52
Title
Change From Baseline in Mean Count Per Minute of Daily Physical Activity Measured by Accelerometer (PA-Ac) Up to Week 16
Description
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).
Time Frame
Baseline up to Week 16
Title
Number of Participants With Treatment-emergent Serious Adverse Events (SAEs)
Description
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.
Time Frame
Up to 56 weeks
Title
Number of Participants With Treatment-emergent Adverse Events (AEs)
Description
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.
Time Frame
Up to 56 weeks
Title
Number of Participants With AEs Leading to Premature Discontinuation of Study Treatment
Description
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.
Time Frame
Up to 56 weeks
Title
Change From Baseline in Systolic and Diastolic Arterial Blood Pressure (BP)
Description
Change from baseline in systolic and diastolic arterial BP at Week 8, Week 16, Week 32 and Week 52 was reported.
Time Frame
Baseline, Week 8, Week 16, Week 32 and Week 52
Title
Change From Baseline in Pulse Rate
Description
Change from baseline in pulse rate at Week 8, Week 16, Week 32 and Week 52 was reported.
Time Frame
Baseline, Week 8, Week 16, Week 32 and Week 52
Title
Change From Baseline in Oxygen Saturation (SpO2)
Description
Change from baseline in SpO2 was reported.
Time Frame
Baseline, Week 8, Week 16, Week 32 and Week 52
Title
Change From Baseline in Body Weight
Description
Change from baseline in body weight was reported.
Time Frame
Baseline, Week 8, Week 16, Week 32 and Week 52
Title
Number of Participants With Treatment-emergent Markedly Abnormal Laboratory Values
Description
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".
Time Frame
Up to 56 weeks
Title
Change From Baseline in Hemoglobin
Description
Change from baseline in hemoglobin was reported.
Time Frame
Baseline, Week 8, Week 16, Week 32 and Week 52
Title
Change From Baseline in Hematocrit
Description
Change from baseline in hematocrit was reported.
Time Frame
Baseline, Week 8, Week 16, Week 32 and Week 52
Title
Change From Baseline in Erythrocytes and Reticulocytes
Description
Change from baseline in erythrocytes and reticulocytes at Week 8, Week 16, Week 32 and Week 52 was reported.
Time Frame
Baseline, Week 8, Week 16, Week 32 and Week 52
Title
Change From Baseline in Leucocytes, Neutrophils, Lymphocytes, Monocytes, Eosinophils, Basophils and Platelets
Description
Change from baseline in leucocytes, neutrophils, lymphocytes, monocytes, eosinophils, basophils and platelets at Week 8, Week 16, Week 32 and Week 52 was reported.
Time Frame
Baseline, Week 8, Week 16, Week 32 and Week 52
Title
Change From Baseline in Prothrombin Time
Description
Change from baseline in prothrombin time was reported.
Time Frame
Baseline, Week 8, Week 16, Week 32 and Week 52
Title
Change From Baseline in Prothrombin International Normalized Ratio
Description
Change from baseline in prothrombin international normalized ratio was reported.
Time Frame
Baseline, Week 8, Week 16, Week 32 and Week 52
Title
Change From Baseline in Alanine Aminotransferase (ALT), Aspartate Aminotransferase (AST) and Alkaline Phosphatase (AP)
Description
Change from baseline in ALT, AST and AP were reported.
Time Frame
Baseline, Week 8, Week 16, Week 32 and Week 52
Title
Change From Baseline in Bilirubin and Direct Bilirubin
Description
Change from baseline in bilirubin and direct bilirubin was reported.
Time Frame
Baseline, Week 8, Week 16, Week 32 and Week 52
Title
Change From Baseline in Gamma Glutamyl Transferase
Description
Change from baseline in gamma glutamyl transferase was reported.
Time Frame
Baseline, Week 8, Week 16, Week 32 and Week 52
Title
Change From Baseline in Creatinine
Description
Change from baseline in creatinine was reported.
Time Frame
Baseline, Week 8, Week 16, Week 32 and Week 52
Title
Change From Baseline in Urea Nitrogen
Description
Change from baseline in urea nitrogen was reported.
Time Frame
Baseline, Week 8, Week 16, Week 32 and Week 52
Title
Change From Baseline in Urate
Description
Change from baseline in urate was reported.
Time Frame
Baseline, Week 8, Week 16, Week 32 and Week 52
Title
Change From Baseline in Glucose, Cholesterol, Triglycerides, Sodium, Potassium, Chloride and Calcium
Description
Change from baseline in glucose, cholesterol, triglycerides, sodium, potassium, chloride and calcium was reported.
Time Frame
Baseline, Week 8, Week 16, Week 32 and Week 52
Title
Change From Baseline in Albumin and Protein
Description
Change from baseline in albumin and protein was reported.
Time Frame
Baseline, Week 8, Week 16, Week 32 and Week 52
Title
Change From Baseline in Alpha Fetoprotein
Description
Change from baseline in alpha fetoprotein was reported.
Time Frame
Baseline, Week 8, Week 16, Week 32 and Week 52
Title
Change From Baseline in Cystatin C
Description
Change from baseline in cystatin C was reported.
Time Frame
Baseline, Week 8, Week 16, Week 32 and Week 52

10. Eligibility

Sex
All
Minimum Age & Unit of Time
12 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
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
Facility Information:
Facility Name
University of Alabama at Birmingham
City
Birmingham
State/Province
Alabama
ZIP/Postal Code
35233-1935
Country
United States
Facility Name
UCLA
City
Los Angeles
State/Province
California
ZIP/Postal Code
90095
Country
United States
Facility Name
Massachusetts General Hospital Heart Center
City
Boston
State/Province
Massachusetts
ZIP/Postal Code
02114
Country
United States
Facility Name
Nationwide Children's Hospital
City
Columbus
State/Province
Ohio
ZIP/Postal Code
43205
Country
United States
Facility Name
Texas Children's Hospital
City
Houston
State/Province
Texas
ZIP/Postal Code
77030-2303
Country
United States
Facility Name
Providence Medical Research Providence Health Care
City
Spokane
State/Province
Washington
ZIP/Postal Code
99202
Country
United States
Facility Name
Royal Adelaide Hospital
City
Adelaide
ZIP/Postal Code
5000
Country
Australia
Facility Name
Royal Prince Alfred Hospital
City
Camperdown
ZIP/Postal Code
2050
Country
Australia
Facility Name
The Prince Charles Hospital, Adult Congenital Heart Disease Unit
City
Chermside
ZIP/Postal Code
4032
Country
Australia
Facility Name
Royal Children's Hospital
City
Parkville
ZIP/Postal Code
3052
Country
Australia
Facility Name
Queensland CHILDREN'S HOSPITAL
City
South Brisbane
ZIP/Postal Code
4101
Country
Australia
Facility Name
Westmead Hospital
City
Westmead
ZIP/Postal Code
2145
Country
Australia
Facility Name
CHU de Québec Université Laval
City
Quebec
ZIP/Postal Code
G1V 4G2
Country
Canada
Facility Name
Beijing Anzhen Hospital
City
Beijing
ZIP/Postal Code
100029
Country
China
Facility Name
Beijing Fuwai Hospital
City
Beijing
ZIP/Postal Code
100037
Country
China
Facility Name
Shanghai Children's Medical Center
City
Shanghai
ZIP/Postal Code
200127
Country
China
Facility Name
Wuhan Asia Heart Hospital
City
Wuhan
ZIP/Postal Code
430022
Country
China
Facility Name
Fakultni nemocnice v Motole
City
Praha 5
ZIP/Postal Code
150 06
Country
Czechia
Facility Name
Rigshospitalet Kardiologisk Klinisk
City
Copenhagen
ZIP/Postal Code
2100
Country
Denmark
Facility Name
CHU Arnaud de Villeneuve
City
Montpellier Cedex 5
ZIP/Postal Code
34295
Country
France
Facility Name
Hôpital Necker - Enfants Malades
City
Paris
ZIP/Postal Code
75015
Country
France
Facility Name
Hôpital Cardiologique Du Haut-Lévêque
City
Pessac
ZIP/Postal Code
33604
Country
France
Facility Name
Deutsches Herzzentrum Berlinklinik Für Angeborene Herzfehler
City
Berlin
ZIP/Postal Code
13353
Country
Germany
Facility Name
Deutsches Herzzentrum München
City
München
ZIP/Postal Code
80636
Country
Germany
Facility Name
Auckland City Hospital
City
Auckland
ZIP/Postal Code
1640
Country
New Zealand
Facility Name
Uniwersyteckie Centrum Kliniczne
City
Gdansk
ZIP/Postal Code
80-952
Country
Poland
Facility Name
Krakowski Szpital Specjalityczny im. Jana Pawla II, Oddzial Kliniczny Chorob Serca i Naczyn
City
Krakow
ZIP/Postal Code
31-202
Country
Poland
Facility Name
Uniwersytecki Szpital Dzieciecy w Krakowie
City
Kraków
ZIP/Postal Code
30-663
Country
Poland
Facility Name
Wojewódzki Szpital Specjalistyczny We Wrocławiu
City
Wrocław
ZIP/Postal Code
51-124
Country
Poland
Facility Name
National Taiwan University Hospital
City
Taipei
ZIP/Postal Code
100
Country
Taiwan
Facility Name
Queen Elizabeth Hospital
City
Birmingham
ZIP/Postal Code
B15 2TH
Country
United Kingdom
Facility Name
Birmingham Children's Hospital
City
Birmingham
ZIP/Postal Code
B4 6NH
Country
United Kingdom

12. IPD Sharing Statement

Plan to Share IPD
No

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

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