NCT01739400: MAESTRO-OL

Clinical Study to Assess the Long-term Safety, Tolerability, and Efficacy of Macitentan in Subjects With Eisenmenger Syndrome

Terminated Phase 3 Results posted Last updated 16 April 2019

What this trial tests

Phase 3 trial testing Macitentan 10 mg tablet, once daily. in Pulmonary Arterial Hypertension in 217 participants. Terminated before completion.

Timeline

10 September 2013

Primary endpoint
12 January 2018

12 January 2018

Quick facts

Lead sponsor	Actelion
Phase	Phase 3
Status	Terminated
Study type	INTERVENTIONAL
Allocation	na
Design	single group
Masking	none
Primary purpose	treatment
Enrollment	217
Start date	10 September 2013
Primary completion	12 January 2018
Estimated completion	12 January 2018
Sites	51 locations across Malaysia, Vietnam, Poland, Philippines, Russia, Mexico, Bulgaria, Portugal

Drugs / interventions tested

• Macitentan 10 mg tablet, once daily. — full drug profile →

Conditions studied

• Pulmonary Arterial Hypertension — all drugs for Pulmonary Arterial Hypertension →

Sponsor

Actelion — full company profile →

Who can join

12 and older, any sex, with Pulmonary Arterial Hypertension. Patients with the condition only — healthy volunteers not accepted.

Results — posted to ClinicalTrials.gov

Per-arm endpoint measurements with 95% confidence intervals where reported. Source: trial results section.

Change in Exercise Capacity as Measured by 6-minute Walking Distance (6MWD) Month 6 and 12 Primary · From baseline in DB parent study (AC-055-305, NCT01743001) up to month 12 in this OL study.

NOTE: The MAESTRO-OL study was exploratory in nature and no primary efficacy and safety endpoint were defined in the clinical protocol. This and the other exploratory efficacy outcome measures posted were selected to be reported as a primary endpoints. All efficacy analyses were considered exploratory. The analyses of the exploratory efficacy endpoints focused on the absolute values and on the change from DB baseline to Week 16 in the DB study and to Month 6 and Month 12 in the OL study. For missing 6MWD values in the OL study, the following imputation rules were applied: If the reason for mis

6MWD at DB study baseline

Group	Value	95% CI
DB-macitentan	370.6	± 74.1
DB-placebo	381.6	± 76.7

6MWD at Week 16 in DB study

Group	Value	95% CI
DB-macitentan	395.1	± 88.4
DB-placebo	399.9	± 80.6

Change in 6MWD from DB study baseline to Week 16

Group	Value	95% CI
DB-macitentan	24.4	± 71.0
DB-placebo	18.2	± 53.0

6MWD at Month 6 in OL study

Group	Value	95% CI
DB-macitentan	396.8	± 96.5
DB-placebo	425.0	± 72.1

Change in 6MWD from DB study baseline to Month 6

Group	Value	95% CI
DB-macitentan	26.2	± 77.9
DB-placebo	43.4	± 51.5

6MWD at Month 12 in OL study

Group	Value	95% CI
DB-macitentan	397.1	± 103.9
DB-placebo	421.5	± 76.5

Change in 6MWD from DB study baseline to Month 12

Group	Value	95% CI
DB-macitentan	26.5	± 79.8
DB-placebo	39.9	± 55.1

Change in WHO Functional Class (FC) at Month 6 and 12 Primary · From baseline in DB parent study (AC-055-305, NCT01743001) up to month 12 in this OL study.

Class I: no symptoms with exercise or at rest. No limitation of activity. Class II: No symptoms at rest but slight limitation with ordinary activities causing symptoms (e.g. short of breath with climbing stairs). Class III: may not have symptoms at rest but activities greatly limited by shortness of breath, fatigue, or near fainting. Class IV: symptoms at rest and inability to carry out any physical activity without symptoms. Patients in class IV manifest signs of right heart failure. For missing WHO FC values in the OL study, the following imputation rules were applied: If the reason for miss

WHO functional class I at DB study baseline

Group	Value	95% CI
DB-macitentan	0
DB-placebo	0

WHO functional class II at DB study baseline

Group	Value	95% CI
DB-macitentan	66
DB-placebo	65

WHO functional class III at DB study baseline

Group	Value	95% CI
DB-macitentan	43
DB-placebo	43

WHO functional class IV at DB study baseline

Group	Value	95% CI
DB-macitentan	0
DB-placebo	0

WHO functional class I at Week 16 in DB study

Group	Value	95% CI
DB-macitentan	3
DB-placebo	1

WHO functional class II at Week 16 in DB study

Group	Value	95% CI
DB-macitentan	70
DB-placebo	77

WHO functional class III at Week 16 in DB study

Group	Value	95% CI
DB-macitentan	36
DB-placebo	30

WHO functional class IV at Week 16 in DB study

Group	Value	95% CI
DB-macitentan	0
DB-placebo	0

Change in Borg Dyspnea Score at Month 6 and 12 Primary · From baseline in DB parent study (AC-055-305, NCT01743001) up to month 12 in this OL study.

The Borg dyspnea score rates the severity of dyspnea (difficult or labored breathing) on a scale from 0 ('Nothing at all') to 10 ('Very, very severe - maximal'). For missing Borg dyspnea index values in the OL study, the following imputation rules were applied: If the reason for missing data was death, a value of 10 was imputed for all Borg visits from the date of death. For any other reasons, the last available value was carried forward.

Borg dyspnea score at DB study baseline

Group	Value	95% CI
DB-macitentan	3.0	± 1.9
DB-placebo	2.9	± 1.8

Borg dyspnea score at Week 16 in DB study

Group	Value	95% CI
DB-macitentan	2.7	± 1.9
DB-placebo	1.9	± 1.6

Change from DB study baseline to Week 16

Group	Value	95% CI
DB-macitentan	-0.3	± 1.4
DB-placebo	-0.2	± 1.5

Borg dyspnea score at Month 6 in OL study

Group	Value	95% CI
DB-macitentan	2.8	± 2.0
DB-placebo	2.5	± 1.8

Change from DB study baseline to Month 6

Group	Value	95% CI
DB-macitentan	-0.1	± 2.0
DB-placebo	-0.4	± 1.5

Borg dyspnea score at Month 12 in OL study

Group	Value	95% CI
DB-macitentan	2.9	± 2.0
DB-placebo	2.6	± 1.9

Change from DB study baseline to Month 12

Group	Value	95% CI
DB-macitentan	-0.1	± 2.1
DB-placebo	-0.3	± 1.6

Change in Peripheral Oxygen Saturation (SpO2) at Rest at Month 6 and 12 Primary · From baseline in DB parent study (AC-055-305, NCT01743001) up to month 12 in this OL study.

No imputation of missing data for SpO2 was applied. Oxygen saturation assessed by pulse oximetry: peripheral oxygen saturation (SpO2) at rest before the 6-minute walk test (6MWT)

SpO2 at DB study baseline

Group	Value	95% CI
DB-macitentan	84.2	± 5.6
DB-placebo	85.4	± 5.0

SpO2 at Week 16 in DB study

Group	Value	95% CI
DB-macitentan	85.3	± 5.8
DB-placebo	85.6	± 5.4

Change in SpO2 from DB study baseline to Week 16

Group	Value	95% CI
DB-macitentan	1.1	± 4.0
DB-placebo	0.2	± 4.5

SpO2 at Month 6 in OL study

Group	Value	95% CI
DB-macitentan	85.9	± 5.9
DB-placebo	87.4	± 5.4

Change in SpO2 from DB study baseline to Month 6

Group	Value	95% CI
DB-macitentan	1.5	± 4.9
DB-placebo	2.0	± 4.3

SpO2 at Month 12 in OL study

Group	Value	95% CI
DB-macitentan	86.4	± 6.3
DB-placebo	87.1	± 5.0

Change in SpO2 from DB study baseline to Month 12

Group	Value	95% CI
DB-macitentan	2.0	± 4.4
DB-placebo	1.6	± 4.9

Adverse events — posted to ClinicalTrials.gov

Time frame: From open label study treatment initiation up to 30 days after study treatment discontinuation (max. 24 months + 30 days).. Reporting threshold: 5%. Adverse-event reports describe events observed during the trial — not all are caused by the drug.

All-enrolled Analysis Set

Serious: 62/217 (29%)

Deaths: 7/217

Serious adverse events (67 terms)

Reaction	System	All-enrolled Analysis Set
Haemoptysis	Respiratory, thoracic and mediastinal disorders	—
Right ventricular failure	Cardiac disorders	—
Pneumonia	Infections and infestations	—
Pulmonary arterial hypertension	Respiratory, thoracic and mediastinal disorders	—
Cardiac failure	Cardiac disorders	—
Chest pain	General disorders	—
Pregnancy	Pregnancy, puerperium and perinatal conditions	—
Pulmonary embolism	Respiratory, thoracic and mediastinal disorders	—
Brain abscess	Infections and infestations	—
Chest discomfort	General disorders	—
Ischaemic stroke	Nervous system disorders	—
Ovarian cyst ruptured	Reproductive system and breast disorders	—
Syncope	Nervous system disorders	—
Abdominal distension	Gastrointestinal disorders	—
Allergy to arthropod sting	Immune system disorders	—
Antineutrophil cytoplasmic antibody positive	Investigations	—
Anxiety	Psychiatric disorders	—
Appendicitis perforated	Infections and infestations	—
Arrhythmia	Cardiac disorders	—
Arterial perforation	Vascular disorders	—
Atrial fibrillation	Cardiac disorders	—
Bronchiectasis	Respiratory, thoracic and mediastinal disorders	—
Bronchitis viral	Infections and infestations	—
Cardiac arrest	Cardiac disorders	—
Cardiogenic shock	Cardiac disorders	—

Other adverse events (12 terms — click to expand)

Reaction	System	All-enrolled Analysis Set
Upper respiratory tract infection	Infections and infestations	—
Headache	Nervous system disorders	—
Haemoptysis	Respiratory, thoracic and mediastinal disorders	—
Cough	Respiratory, thoracic and mediastinal disorders	—
Viral upper respiratory tract infection	Infections and infestations	—
Bronchitis	Infections and infestations	—
Haemoglobin decreased	Investigations	—
Diarrhoea	Gastrointestinal disorders	—
Dizziness	Nervous system disorders	—
Oedema peripheral	General disorders	—
Chest pain	General disorders	—
Fatigue	General disorders	—

Most-reported serious reactions: Haemoptysis, Right ventricular failure, Pneumonia, Pulmonary arterial hypertension, Cardiac failure, Chest pain, Pregnancy, Pulmonary embolism.

Data from ClinicalTrials.gov NCT01739400 adverse events section.

Sponsor's own description

Long-term study to evaluate if macitentan is safe, tolerable and efficient enough to be used for treatment of Eisenmenger syndrome.

Publications & conference data

2 peer-reviewed publications reference this trial (live from Europe PMC):

1. Evaluation of Macitentan in Patients With Eisenmenger Syndrome.
   Gatzoulis MA, Landzberg M, Beghetti M, Berger RM, et al · · 2019 · cited 83× · PMID 30586694 · DOI 10.1161/circulationaha.118.033575
2. Treatment of pulmonary arterial hypertension with the dual endothelin receptor antagonist macitentan: clinical evidence and experience.
   Belge C, Delcroix M. · · 2019 · cited 16× · PMID 30736726 · DOI 10.1177/1753466618823440