NCT02070991: MELODY-1

Clinical Study to Evaluate the Safety and Tolerability of Macitentan in Subjects With Combined Pre- and Post-capillary Pulmonary Hypertension (CpcPH) Due to Left Ventricular Dysfunction

Completed Phase 2 Results posted Last updated 15 May 2019

What this trial tests

Phase 2 trial testing Macitentan in Pulmonary Hypertension in 63 participants. Completed in 1 November 2015.

Timeline

1 July 2014

Primary endpoint
1 November 2015

1 November 2015

Quick facts

Lead sponsor	Actelion
Phase	Phase 2
Status	Completed
Study type	INTERVENTIONAL
Allocation	randomized
Design	parallel
Masking	quadruple
Primary purpose	treatment
Enrollment	63
Start date	1 July 2014
Primary completion	1 November 2015
Estimated completion	1 November 2015
Sites	32 locations across France, Italy, Belgium, Austria, Germany, Israel, Canada, Switzerland

Drugs / interventions tested

• Macitentan (MACITENTAN) — full drug profile →
• Placebo

Conditions studied

• Pulmonary Hypertension — all drugs for Pulmonary Hypertension →

Sponsor

Actelion — full company profile →

Who can join

18 and older, any sex, with Pulmonary 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.

Number of Participants Experiencing Significant Fluid Retention or Worsening in NYHA Functional Class (FC) up to End-of-treatment Primary · From randomization up to End-of-Study (Week 12 + 30 days follow-up) plus 1 calendar day

The main endpoint is the number of participants who had at least one of the following: A) significant fluid retention, defined as increase in body weight at any time by ≥ 5% or ≥ 5 kg from baseline due to fluid overload and/or parenteral administration of diuretics. B) Worsening of NYHA functional class from baseline.

Total participants with at least one condition

Group	Value	95% CI
Macitentan	7
Placebo	4

Participants with fluid retention

Group	Value	95% CI
Macitentan	7
Placebo	3

Participants with worsening in NYHA FC

Group	Value	95% CI
Macitentan	1
Placebo	2

Participants with both conditions

Group	Value	95% CI
Macitentan	1
Placebo	1

NT-proBNP at Week 12 Expressed as Percent of Baseline NT-proBNP at Rest Secondary · From randomization up to end of treatment period (Week 12)

Group	Value	95% CI
Macitentan	91.56	72.37 – 115.83
Placebo	118.90	92.53 – 152.78

PVR at Rest at Week 12 Expressed as Percent of Baseline PVR at Rest Secondary · From randomization up to end of treatment period (Week 12)

Pulmonary vascular resistance (PVR) was assessed at rest by right heart catheterization (RHC).

Group	Value	95% CI
Macitentan	66.31	56.15 – 78.30
Placebo	71.23	51.35 – 98.81

Change From Baseline to Week 12 in Mean Pulmonary Arterial Pressure (mPAP) Secondary · From randomization up to end of treatment period (Week 12)

mPAP at baseline

Group	Value	95% CI
Macitentan	44.6	40.7 – 48.6
Placebo	45.9	41.7 – 50.1

mPAP at Week 12

Group	Value	95% CI
Macitentan	41.1	36.2 – 46.0
Placebo	42.1	37.5 – 46.7

Change in mPAP from baseline to Week 12

Group	Value	95% CI
Macitentan	-3.5	-6.1 – -0.9
Placebo	-3.8	-7.5 – -0.1

Change From Baseline to Week 12 in Mean Right Atrial Pressure (mRAP) Secondary · From randomization up to end of treatment period (Week 12)

mRAP at baseline

Group	Value	95% CI
Macitentan	12.1	10.0 – 14.3
Placebo	13.0	11.0 – 14.9

mRAP at Week 12

Group	Value	95% CI
Macitentan	11.2	8.7 – 13.8
Placebo	11.3	9.2 – 13.5

Change in mRAP from baseline to Week 12

Group	Value	95% CI
Macitentan	-0.9	-3.5 – 1.7
Placebo	-1.6	-3.3 – 0.0

Change From Baseline to Week 12 in Pulmonary Artery Wedge Pressure (PAWP) Secondary · From randomization up to end of treatment period (Week 12)

PAWP at baseline

Group	Value	95% CI
Macitentan	19.1	17.4 – 20.7
Placebo	19.7	18.2 – 21.2

PAWP at Week 12

Group	Value	95% CI
Macitentan	19.9	16.6 – 23.1
Placebo	20.8	17.8 – 23.7

Change in PAWP from baseline to Week 12

Group	Value	95% CI
Macitentan	0.8	-2.3 – 3.9
Placebo	1.1	-1.6 – 3.8

Change From Baseline to Week 12 in Cardiac Index (CI) Secondary · From randomization up to end of treatment period (Week 12)

CI at baseline

Group	Value	95% CI
Macitentan	2.32	2.02 – 2.61
Placebo	2.33	2.09 – 2.57

CI at Week 12

Group	Value	95% CI
Macitentan	2.69	2.36 – 3.02
Placebo	2.30	2.03 – 2.57

Change in CI from baseline to Week 12

Group	Value	95% CI
Macitentan	0.37	0.14 – 0.60
Placebo	-0.03	-0.22 – 0.16

Change From Baseline to Week 12 in Diastolic Pulmonary Vascular Pressure Gradient (DPG) Secondary · From randomization up to end of treatment period (Week 12)

DPG at baseline

Group	Value	95% CI
Macitentan	11.8	9.0 – 14.5
Placebo	11.4	9.5 – 13.2

DPG at Week 12

Group	Value	95% CI
Macitentan	7.0	4.2 – 9.8
Placebo	7.0	3.7 – 10.4

Change in DPG from baseline to Week 12

Group	Value	95% CI
Macitentan	-4.8	-7.2 – -2.3
Placebo	-4.3	-7.5 – -1.1

Adverse events — posted to ClinicalTrials.gov

Time frame: From study treatment initiation up to 30 days after study treatment discontinuation (Week 12 + 30 days). Reporting threshold: 5%. Adverse-event reports describe events observed during the trial — not all are caused by the drug.

Macitentan

Serious: 11/31 (35%)

Deaths: 2/31

Placebo

Serious: 6/32 (19%)

Deaths: 0/32

Serious adverse events (21 terms)

Reaction	System	Macitentan	Placebo
Pneumonia	Infections and infestations	—	—
Atrial fibrillation	Cardiac disorders	—	—
Cardiac failure acute	Cardiac disorders	—	—
Cardiac failure congestive	Cardiac disorders	—	—
Cardiorenal syndrome	Cardiac disorders	—	—
Left ventricular failure	Cardiac disorders	—	—
Right ventricular failure	Cardiac disorders	—	—
Ventricular tachycardia	Cardiac disorders	—	—
Mouth haemorrhage	Gastrointestinal disorders	—	—
Oedema peripheral	General disorders	—	—
Sudden death	General disorders	—	—
Respiratory tract infection bacterial	Infections and infestations	—	—
Fall	Injury, poisoning and procedural complications	—	—
Hypoglycaemia	Metabolism and nutrition disorders	—	—
Acute kidney injury	Renal and urinary disorders	—	—
Chronic respiratory failure	Respiratory, thoracic and mediastinal disorders	—	—
Pulmonary congestion	Respiratory, thoracic and mediastinal disorders	—	—
Pulmonary mass	Respiratory, thoracic and mediastinal disorders	—	—
Pulmonary oedema	Respiratory, thoracic and mediastinal disorders	—	—
Respiratory failure	Respiratory, thoracic and mediastinal disorders	—	—
Jugular vein thrombosis	Vascular disorders	—	—

Other adverse events (19 terms — click to expand)

Reaction	System	Macitentan	Placebo
Dyspnoea	Respiratory, thoracic and mediastinal disorders	—	—
Diarrhoea	Gastrointestinal disorders	—	—
Oedema peripheral	General disorders	—	—
Anaemia	Blood and lymphatic system disorders	—	—
Atrial fibrillation	Cardiac disorders	—	—
Mitral valve incompetence	Cardiac disorders	—	—
Nausea	Gastrointestinal disorders	—	—
Fatigue	General disorders	—	—
Respiratory tract infection	Infections and infestations	—	—
Urinary tract infection	Infections and infestations	—	—
Blood bilirubin increased	Investigations	—	—
Haemoglobin decreased	Investigations	—	—
Walking distance test abnormal	Investigations	—	—
Fluid retention	Metabolism and nutrition disorders	—	—
Hypokalaemia	Metabolism and nutrition disorders	—	—
Hepatic neoplasm	Neoplasms benign, malignant and unspecified (incl cysts and polyps)	—	—
Dizziness	Nervous system disorders	—	—
Cough	Respiratory, thoracic and mediastinal disorders	—	—
Pleural effusion	Respiratory, thoracic and mediastinal disorders	—	—

Most-reported serious reactions: Pneumonia, Atrial fibrillation, Cardiac failure acute, Cardiac failure congestive, Cardiorenal syndrome, Left ventricular failure, Right ventricular failure, Ventricular tachycardia.

Data from ClinicalTrials.gov NCT02070991 adverse events section.

Sponsor's own description

Study to evaluate if macitentan is safe and tolerable enough to be used for treatment of subjects with combined pre- and post-capillary pulmonary hypertension (CpcPH) due to left ventricular dysfunction.

Publications & conference data

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

1. Left ventricular heart failure and pulmonary hypertension.
   Rosenkranz S, Gibbs JS, Wachter R, De Marco T, et al · · 2016 · cited 472× · PMID 26508169 · DOI 10.1093/eurheartj/ehv512
2. Intersection of Pulmonary Hypertension and Right Ventricular Dysfunction in Patients on Left Ventricular Assist Device Support: Is There a Role for Pulmonary Vasodilators?
   Sparrow CT, LaRue SJ, Schilling JD. · · 2018 · cited 29× · PMID 29321132 · DOI 10.1161/circheartfailure.117.004255
3. Identifying At-Risk Patients with Combined Pre- and Postcapillary Pulmonary Hypertension Using Interventricular Septal Angle at Cardiac MRI.
   Johns CS, Wild JM, Rajaram S, Tubman E, et al · · 2018 · cited 25× · PMID 29969067 · DOI 10.1148/radiol.2018180120
4. Pulmonary hypertension in patients with heart failure and preserved ejection fraction: differential diagnosis and management.
   Hussain N, Charalampopoulos A, Ramjug S, Condliffe R, et al · · 2016 · cited 19× · PMID 27162611 · DOI 10.1086/685021
5. Controversies in pulmonary hypertension due to left heart disease.
   Cheli M, Vachiery JL. · · 2015 · cited 15× · PMID 25705390 · DOI 10.12703/p7-07
6. A roadmap for therapeutic discovery in pulmonary hypertension associated with left heart failure. A scientific statement of the Heart Failure Association (HFA) of the ESC and the ESC Working Group on Pulmonary Circulation & Right Ventricular Function.
   Ameri P, Mercurio V, Pollesello P, Anker MS, et al · · 2024 · cited 12× · PMID 38639017 · DOI 10.1002/ejhf.3236